{"aops":[{"id":199,"title":"ER mediated breast cancer AOP ","short_name":"ER mediated breast cancer AOP ","corresponding_author_id":236,"abstract":"","created_at":"2016-11-29T18:41:17.000-05:00","updated_at":"2023-04-29T16:02:59.000-04:00","status_id":5,"authors":"","applicability_of_the_aop":"","key_event_essentiality":"","weight_of_evidence_summary":"","quantitative_considerations":"","optional_considerations":"","references":"","overall_assessment":"","background":"","user_defined_mie":"","user_defined_ao":"","oecd_project":null,"oecd_status_id":null,"graphical_representation_image_uid":null,"saaop_status_id":3,"legacy":true,"overall_assessment_file_uid":null,"changed_at":null,"development_strategy":null,"known_modulating_factors":null,"assigned_license_id":170,"handbook_id":1,"project_129":false},{"id":200,"title":"Estrogen receptor activation leading to breast cancer  ","short_name":"ER activation to breast cancer ","corresponding_author_id":236,"abstract":"\u003cp\u003eEndocrine disrupting chemicals (EDC), particularly estrogen receptor (ER) agonists, are thought to contribute to the incidence of breast cancer. The majority (approximately 75 percent) of breast cancer cases express the estrogen receptor. Both animal and human studies strongly support that activation of the estrogen receptor stimulates breast cancer development and progression. We created the ER-mediated breast cancer AOP to frame how ER activation (the MIE) leads to breast cancer (the AO). For more information regarding the AOP, refer to the Morgan \u0026amp; Johnson et al. (2015) citation.\u003c/p\u003e\r\n\r\n\u003cp\u003eActivation of the estrogen receptor in breast epithelial cells stimulates genomic and non-genomic changes, which alters epithelial gene expression and subsequent protein production. Consequently, breast epithelial cells experience increased proliferation, decreased apoptosis, dysfunction of mitochondrial dynamics, increased DNA damage, increased cell motility, and increased oxidative stress. These cellular changes translate to a tissue level where ductal hyperplasia and cell invasion is increased.\u003c/p\u003e\r\n\r\n\u003cp\u003eWhile breast epithelial cells are the cancer cell type in ER+ adenocarcinomas, other cell types of the microenvironment interact with the AOP. For example, endothelial cells express ER and upon ER activation, undergo gene expression and protein production changes. Consequently, endothelial cell proliferation and migration is increased, leading to increased angiogenesis, which supports the proliferation of breast cancer epithelial cells. While estrogens do not target fibroblasts, adipocytes, or macrophages directly, they become activated as breast cancer progresses. It is not well understood if there is a direct relationship between estrogen signaling and stromal cell activation, however, activated cells stimulate cancer cell proliferation, influence chemical response, increase cell motility, and rearrange the extracellular matrix. Moreover, adipocytes contribute to the AOP through metabolism of testosterone to estrogen, and fibroblasts have been shown to regulate estrogen receptor regulated genes in epithelial cells. Therefore, due to how the breast microenvironment interacts with and stimulates the AOP, we have included activation of these cell types into our framework.\u003c/p\u003e\r\n\r\n\u003cp\u003eOverall, the ER-mediated breast cancer AOP is a useful framework that can identify both readouts and components of the breast microenvironment that are important in disease progression.\u003c/p\u003e\r\n","created_at":"2016-11-29T18:41:17.000-05:00","updated_at":"2025-04-28T15:01:24.000-04:00","status_id":3,"authors":"\u003cp\u003eMolly M. Morgan, Brian P. Johnson, David J. Beebe\u003c/p\u003e\r\n\r\n\u003cp\u003eDepartment of Biomedical Engineering, College of Engineering, University of Wisconsin-Madison\u003c/p\u003e\r\n","applicability_of_the_aop":"\u003cp\u003e\u003cstrong\u003eSex.\u003c/strong\u003e While females have a higher incidence of breast cancer, estrogen-receptor mediated breast cancer can occur in males and females.\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003cstrong\u003eLife stages.\u003c/strong\u003e Breast cancer affects adult women and men. Older adult women have a higher probability of having an ER+ breast cancer (vs. ER-) than younger adult women.\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003cstrong\u003eTaxonomic applicability.\u003c/strong\u003e Breast cancer occurs naturally in humans, cats, and dogs. \u003cem\u003eIn vivo\u003c/em\u003e studies primarily study breast cancer in mice.\u003c/p\u003e\r\n","key_event_essentiality":"","weight_of_evidence_summary":"\u003cp\u003eThe weight of evidence for the KERs related to epithelial cells is mostly strong. The KERs between ER activation, motility, and invasion were labeled as a moderate weight of evidence due to discrepancies in the literature regarding whether ER activation decreases motility/invasion, vs. increases motility/invasion. ER activation leading to non-genomic signaling was labeled as moderate due to the limited evidence supporting this KER. For non-epithelial cell types, we labeled the KERs relationship as mostly weak. ER activation has direct effects on endothelial cells as they express ER and several studies have correlated ER activation with increased proliferation, migration, and angiogenesis. Macrophages, fibroblasts, and adipocytes are influenced by and stimulate breast cancer progression, however, the exact correlation between ER activation and these events is still unclear.\u003c/p\u003e\r\n\r\n\u003ch3\u003e\u0026nbsp;\u003c/h3\u003e\r\n","quantitative_considerations":"","optional_considerations":"","references":"\u003cp\u003eAboussekhra, A. (2011). Role of cancer-associated fibroblasts in breast cancer development and prognosis. Int J Dev Biol, 55(7-9), 841-849. Albini, A., Graf, J., Kitten, G. T., Kleinman, H. K., Martin, G. R., Veillette, A., et al. (1986). 17 beta-estradiol regulates and v-Ha-ras transfection constitutively enhances MCF7 breast cancer cell interactions with basement membrane. Proc Natl Acad Sci U S A, 83(21), 8182-8186. Applanat, M. P., Buteau-Lozano, H., Herve, M. 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Breast Cancer Research, 7(1).\u003c/p\u003e\r\n","overall_assessment":"","background":"","user_defined_mie":"1181: Activation, Estrogen receptor","user_defined_ao":"1193: N/A, Breast Cancer","oecd_project":"","oecd_status_id":null,"graphical_representation_image_uid":"2016/11/29/11dAop-200.jpg","saaop_status_id":3,"legacy":true,"overall_assessment_file_uid":null,"changed_at":"2025-04-28T15:01:24.000-04:00","development_strategy":null,"known_modulating_factors":null,"assigned_license_id":171,"handbook_id":1,"project_129":false},{"id":293,"title":"Increased DNA damage leading to increased risk of breast cancer","short_name":"Increased DNA damage leading to breast cancer","corresponding_author_id":814,"abstract":"\u003cp\u003eKnowledge about established breast carcinogens can support improved 21\u003csup\u003est\u003c/sup\u003e century toxicological testing methods by identifying key mechanistic events. Ionizing radiation (IR) increases the risk of breast cancer, especially for women and for exposure at younger ages. We used the Adverse Outcome Pathway (AOP) framework to outline and evaluate the evidence linking ionizing radiation with breast cancer from molecular initiating events (MIE) to the adverse outcome (AO) through intermediate key events (KE). We identified prospective key events using recent literature on ionizing radiation and carcinogenesis, focusing on review articles. We searched PubMed for each key event and ionizing radiation, and used references cited in the resulting papers and targeted searches with related key words to identify additional papers. We manually curated publications and evaluated data quality. The AOP specifies that ionizing radiation directly and indirectly causes DNA damage and increases production of reactive oxygen and nitrogen species (RONS), and these are designated as MIEs.\u0026nbsp; RONS lead to DNA damage (MIE) which leads to mutations (KE). \u0026nbsp;Proliferation (KE) amplifies the effects of DNA damage and mutations leading to the AO of breast cancer. Separately, RONS (and DNA damage) also increase inflammation (KE). Inflammation contributes to direct and indirect effects (effects in cells not directly reached by IR) via positive feedback to RONS and DNA damage, and separately increases proliferation and the AO through pro-carcinogenic effects on cells and tissue. These MIEs and KEs overlap at multiple points with events characteristic of \u0026ldquo;background\u0026rdquo; induction of breast carcinogenesis, including hormone-responsive proliferation, oxidative activity, and DNA damage. These overlaps make the breast particularly susceptible to ionizing radiation and reinforce the importance of these MIEs and KEs as part of toxicological panels for carcinogenicity. The AOP identifies areas for additional research, including better description of the time and dose-dependence of MIEs and KEs in mammary tissues directly and indirectly exposed to IR.\u003c/p\u003e\r\n\r\n\u003cp\u003eThis AOP extends the characteristics of mammary carcinogens beyond DNA damage, highlighting the important role in breast cancer of chemicals that increase RONS, cell proliferation, and inflammation. Chemicals that increase these biological processes should be considered potential breast carcinogens, and predictive methods should be developed to identify chemicals that increase these processes. Ultimately, this AOP will improve methods that predict chemical breast carcinogens so that exposure can be reduced.\u003c/p\u003e\r\n","created_at":"2019-05-03T10:20:11.000-04:00","updated_at":"2023-04-29T16:03:02.000-04:00","status_id":5,"authors":"\u003cp\u003eJessica S. Helm\u003csup\u003e*\u003c/sup\u003e and Ruthann A. Rudel\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003csup\u003e*\u003c/sup\u003eSilent Spring Institute, Newton, MA 02460\u003c/p\u003e\r\n","applicability_of_the_aop":"\u003cp\u003eWhile the key events described here are likely relevant to all tissues after exposure to IR, it is particularly relevant to the female mammary gland. While ionizing radiation causes many kinds of cancers including leukemia, lung, bladder, and thyroid cancers (BEIR 2006; Preston, Ron et al. 2007), breast cancers are among the cancers most increased by exposure to ionizing radiation (Preston, Ron et al. 2007).\u003c/p\u003e\r\n\r\n\u003cp\u003eThe lengthy and hormone-dependent developmental trajectory of the mammary gland is likely to be a major factor in its susceptibility to breast cancer. Numerous epidemiological and laboratory studies support the requirement for ovarian hormones in the risk of breast cancer from ionizing radiation (Grant, Cologne et al. 2018). Although at first examination breast cancer from ionizing radiation and hormones involve very different processes, in fact the hormone-dependent and ionizing radiation pathways of carcinogenesis intersect at multiple points that are part of breast development leaving the hormone-exposed breast more vulnerable to radiation. Two studies in humans and rats also suggest that IR can increase long term concentrations of circulating estrogen which would further amplify any additive effects, although additional evidence is needed (Suman, Johnson et al. 2012; Grant, Cologne et al. 2018).\u003c/p\u003e\r\n\r\n\u003cp\u003eOne major mechanism promoting breast cancer from ionizing radiation is the proliferation of breast stem cells. Stem cells are considered to be important to initiation because of their long life and capacity to pass on mutations to many progeny. Breast tissue is responsive to estrogen and progesterone, reproductive hormones that rise at puberty and stimulate cellular proliferation with each reproductive cycle and in pregnancy. These hormonal proliferative cycles increase the risk of cancer in breast tissue (Brisken, Hess et al. 2015). IR increases the long term proliferation of stem cells in pubertal but not adult mammary gland (Nguyen, Oketch-Rabah et al. 2011; Datta, Hyduke et al. 2012; Snijders, Marchetti et al. 2012; Suman, Johnson et al. 2012; Tang, Fernandez-Garcia et al. 2014). Replication of stem cells in the IR-exposed breast is therefore particularly elevated during puberty, likely contributing to the increased susceptibility to breast cancer from IR at this age.\u003c/p\u003e\r\n\r\n\u003cp\u003eAnother vulnerability of the breast to IR is a byproduct of proliferation: mutations. Replication itself increases the likelihood of mutations, which add to mutations arising from IR and increase the likelihood of oncogenic transformation (Atashgaran, Wrin et al. 2016). Furthermore, the high replication rate of mammary gland epithelial cells during puberty and pregnancy increases reliance on homologous recombination pathways (Kass, Lim et al. 2016). Disruption of these HR processes by IR-induced mutation or increased demand for repair can increase mutation rates and increase tumorigenesis (Mahdi, Huo et al. 2018). This disruption is particularly relevant for mammary stem cells which are highly replicating and dependent on HR but shift to NHEJ to respond to DNA damage from IR (Chang, Zhang et al. 2015). The consequence of mutations in stem cells is significant, since these cells can clonally expand to generate many mutated progeny. However, errors in stem cell division may not be the sole or primary factor driving cancer from radiation, since excess cancer risk for solid cancers at different sites from the atomic bomb are not clearly related to the number of stem cell divisions at that site (Tomasetti, Li et al. 2017).\u003c/p\u003e\r\n\r\n\u003cp\u003eThe elevated estrogen associated with development and the estrous cycle may also have direct effects that further complement the carcinogenic effects of IR. Estrogen directly increases oxidative stress in virgin (but not parous) mice (Yuan, Dietrich et al. 2016), interferes with DNA repair (Pedram, Razandi et al. 2009; Li, Chen et al. 2014) increases mutations (Mailander, Meza et al. 2006), and increases TGF-b (Jerry, Dunphy et al. 2010). Each of these effects would increase the impact of the same events arising from IR alone.\u003c/p\u003e\r\n\r\n\u003cp\u003eInflammation from the estrous cycle may also contribute to tumorigenesis following IR. Cytokines and macrophages play an integral role in mammary gland development and ductal elaboration, with alternating inflammatory, immune surveillance, and phagocytic activity occurring over each estrous cycle (Hodson, Chua et al. 2013; Atashgaran, Wrin et al. 2016; Brady, Chuntova et al. 2016). This inflammation could potentially increase IR-induced DNA damage and mutations and promote tumorigenic and invasive characteristics.\u003c/p\u003e\r\n\r\n\u003cp\u003eThe enhancement of IR induced tumorigenesis by the estrous cycle may be replicated or further enhanced by exogenous endocrine disrupting chemicals. Indeed, evidence suggests that BPA (and presumably other estrogenic chemicals) exposure in utero can increase the mammary gland\u0026rsquo;s response to progesterone during puberty (Brisken, Hess et al. 2015). This enhancement would presumably also increase the risk of breast cancer from ionizing radiation, since that risk increases with estrogen exposure and the number of menstrual cycles.\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003cstrong\u003eUncertainty arising from extrapolating from rodent and human in vitro studies to human biology\u003c/strong\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003eUncertainty in this pathway arises from inconsistencies in carcinogenesis between rodent and mouse species and strains and from incomplete information about the same mechanisms operating in humans. This raises questions about whether all evidence should be weighted equally.\u003c/p\u003e\r\n\r\n\u003cp\u003eAlmost half of the data included here is from in vitro experiments on human primary or cultured cells, which should have a high degree of relevance for this pathway in humans.\u0026nbsp; However, most of the human cells are not from mammary gland, and most of the mammary gland derived cells are cancer or immortalized cells that will not respond in exactly the same way as primary cells. Even this human data should therefore be interpreted with some caution.\u003c/p\u003e\r\n\r\n\u003cp\u003eMost of the remaining data in this AOP is from mice, with a relatively small number of rat studies. As a breast cancer model, mice share important characteristics with humans (Medina 2007; Imaoka, Nishimura et al. 2009). Mice and humans share similar epithelial cell types (Lim, Wu et al. 2010) and a similar developmental regime with the bulk of epithelial development occurring postnatally and accelerating during puberty, with differentiation during pregnancy (Medina 2007). Tumors in humans originate in the terminal ductal lobular unit, a structure that includes the lobule with secretory alveoli and the start of the collecting duct. The developmental terminal end bud structure is thought to be particularly vulnerable to carcinogens because of the presence of stem cells and proliferation, although it is not the only possible site of initiation. Similarly, tumors in mice originate in predominantly in alveoli as well as terminal end buds and small ducts (Medina 2007). Humans are more susceptible to carcinogens around puberty, and pregnancy is protective. Evidence on the role of development and reproduction in mammary carcinogenesis in mice is limited compared with rats but is consistent with sensitivity to radiation around puberty (Imaoka, Nishimura et al. 2009), and parity is protective for chemical carcinogens (Medina 2007). In addition, proliferation contributes to carcinogenesis in both mice and humans (Medina 2007).\u003c/p\u003e\r\n\r\n\u003cp\u003eHowever, mice differ from humans in some notable ways (Medina 2007). Mammary tumors are not common in mice, so susceptible strains or tumor-promoting viruses are used to increase spontaneous incidence and response to carcinogenic stimuli. This difference may be partially attributable to hormone responsiveness of tumors. Although tumors in mice depend on hormones for development, breast cancers in rats and humans are frequently hormone receptor positive, while mammary tumors in mice are not (Nandi, Guzman et al. 1995; Medina 2007; Imaoka, Nishimura et al. 2009).\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_1\"\u003eAtashgaran, V., J. Wrin, et al. (2016). \u0026quot;Dissecting the Biology of Menstrual Cycle-Associated Breast Cancer Risk.\u0026quot; Front Oncol 6: 267.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_2\"\u003eBrady, N. J., P. Chuntova, et al. (2016). \u0026quot;Macrophages: Regulators of the Inflammatory Microenvironment during Mammary Gland Development and Breast Cancer.\u0026quot; Mediators Inflamm 2016: 4549676.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_3\"\u003eBrisken, C., K. Hess, et al. (2015). \u0026quot;Progesterone and Overlooked Endocrine Pathways in Breast Cancer Pathogenesis.\u0026quot; Endocrinology 156(10): 3442-3450.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_4\"\u003eChang, C. H., M. Zhang, et al. (2015). \u0026quot;Mammary Stem Cells and Tumor-Initiating Cells Are More Resistant to Apoptosis and Exhibit Increased DNA Repair Activity in Response to DNA Damage.\u0026quot; Stem Cell Reports 5(3): 378-391.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_5\"\u003eCommittee to Assess Health Risks from Exposure to Low Levels of Ionizing Radiation (2006). Health risks from exposure to low levels of ionizing radiation : BEIR VII, Phase 2, National Research Council of the National Academies.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_6\"\u003eDatta, K., D. R. Hyduke, et al. (2012). \u0026quot;Exposure to ionizing radiation induced persistent gene expression changes in mouse mammary gland.\u0026quot; Radiat Oncol 7: 205.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_7\"\u003eGrant, E. J., J. B. Cologne, et al. (2018). \u0026quot;Bioavailable serum estradiol may alter radiation risk of postmenopausal breast cancer: a nested case-control study.\u0026quot; International journal of radiation biology 94(2): 97-105.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_8\"\u003eHodson, L. J., A. C. Chua, et al. (2013). \u0026quot;Macrophage phenotype in the mammary gland fluctuates over the course of the estrous cycle and is regulated by ovarian steroid hormones.\u0026quot; Biol Reprod 89(3): 65.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_9\"\u003eImaoka, T., M. Nishimura, et al. (2009). \u0026quot;Radiation-induced mammary carcinogenesis in rodent models: what\u0026#39;s different from chemical carcinogenesis?\u0026quot; J Radiat Res 50(4): 281-293.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_10\"\u003eJerry, D. J., K. A. Dunphy, et al. (2010). \u0026quot;Estrogens, regulation of p53 and breast cancer risk: a balancing act.\u0026quot; Cellular and molecular life sciences : CMLS 67(7): 1017-1023.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_11\"\u003eKass, E. M., P. X. Lim, et al. (2016). \u0026quot;Robust homology-directed repair within mouse mammary tissue is not specifically affected by Brca2 mutation.\u0026quot; Nat Commun 7: 13241.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_12\"\u003eLi, Z., K. Chen, et al. (2014). \u0026quot;Cyclin D1 integrates estrogen-mediated DNA damage repair signaling.\u0026quot; Cancer Res 74(14): 3959-3970.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_13\"\u003eLim, E., D. Wu, et al. (2010). \u0026quot;Transcriptome analyses of mouse and human mammary cell subpopulations reveal multiple conserved genes and pathways.\u0026quot; Breast cancer research : BCR 12(2): R21.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_14\"\u003eMahdi, A. H., Y. Huo, et al. (2018). \u0026quot;Evidence of Intertissue Differences in the DNA Damage Response and the Pro-oncogenic Role of NF-kappaB in Mice with Disengaged BRCA1-PALB2 Interaction.\u0026quot; Cancer Res 78(14): 3969-3981.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_15\"\u003eMailander, P. C., J. L. Meza, et al. (2006). \u0026quot;Induction of A.T to G.C mutations by erroneous repair of depurinated DNA following estrogen treatment of the mammary gland of ACI rats.\u0026quot; The Journal of steroid biochemistry and molecular biology 101(4-5): 204-215.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_16\"\u003eMedina, D. (2007). \u0026quot;Chemical carcinogenesis of rat and mouse mammary glands.\u0026quot; Breast Dis 28: 63-68.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_17\"\u003eNandi, S., R. C. Guzman, et al. (1995). \u0026quot;Hormones and mammary carcinogenesis in mice, rats, and humans: a unifying hypothesis.\u0026quot; Proceedings of the National Academy of Sciences of the United States of America 92(9): 3650-3657.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_18\"\u003eNguyen, D. H., H. A. Oketch-Rabah, et al. (2011). \u0026quot;Radiation acts on the microenvironment to affect breast carcinogenesis by distinct mechanisms that decrease cancer latency and affect tumor type.\u0026quot; Cancer Cell 19(5): 640-651.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_19\"\u003ePedram, A., M. Razandi, et al. (2009). \u0026quot;Estrogen inhibits ATR signaling to cell cycle checkpoints and DNA repair.\u0026quot; Mol Biol Cell 20(14): 3374-3389.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_20\"\u003ePreston, D. L., E. Ron, et al. (2007). \u0026quot;Solid cancer incidence in atomic bomb survivors: 1958-1998.\u0026quot; Radiation research 168(1): 1-64.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_21\"\u003eSnijders, A. M., F. Marchetti, et al. (2012). \u0026quot;Genetic differences in transcript responses to low-dose ionizing radiation identify tissue functions associated with breast cancer susceptibility.\u0026quot; PLoS One 7(10): e45394.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_22\"\u003eSuman, S., M. D. Johnson, et al. (2012). \u0026quot;Exposure to ionizing radiation causes long-term increase in serum estradiol and activation of PI3K-Akt signaling pathway in mouse mammary gland.\u0026quot; International journal of radiation oncology, biology, physics 84(2): 500-507.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_23\"\u003eTang, J., I. Fernandez-Garcia, et al. (2014). \u0026quot;Irradiation of juvenile, but not adult, mammary gland increases stem cell self-renewal and estrogen receptor negative tumors.\u0026quot; Stem Cells 32(3): 649-661.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_24\"\u003eTomasetti, C., L. Li, et al. (2017). \u0026quot;Stem cell divisions, somatic mutations, cancer etiology, and cancer prevention.\u0026quot; Science 355(6331): 1330-1334.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_25\"\u003eYuan, L., A. K. Dietrich, et al. (2016). \u0026quot;17beta-Estradiol alters oxidative damage and oxidative stress response protein expression in the mouse mammary gland.\u0026quot; Mol Cell Endocrinol 426: 11-21.\u003c/a\u003e\u003c/p\u003e\r\n","key_event_essentiality":"\u003cp\u003eEssentiality of the key events\u003c/p\u003e\r\n\r\n\u003cp\u003eIR appears to be a \u0026ldquo;complete\u0026rdquo; carcinogen in the mammary gland in that the toxin acts as an initiator through the formation of oxidative stress and pro-mutagenic DNA damage and (the MIEs) and as a promoter through increasing inflammation and proliferation, similar to many chemical carcinogens (Russo and Russo 1996). We have high confidence in the evidence linking stressor (IR) with adverse outcome (breast cancer). \u0026nbsp;The weight of evidence for the first pathway from RONS to DNA damage, Mutation, and Proliferation is High while the weight of evidence for the second pathway from RONS to Inflammation to Proliferation and Breast Cancer is Moderate. These evaluations are based on the supporting evidence for all KEs and the considerations in Annex 1, and based on the need for additional evidence in the essentiality of Inflammation for the genesis of breast cancer.\u003c/p\u003e\r\n\r\n\u003ctable border=\"1\" cellpadding=\"0\" cellspacing=\"0\"\u003e\r\n\t\u003ctbody\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"height:35px; width:111px\"\u003e\r\n\t\t\t\u003cp\u003e\u0026nbsp;\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"height:35px; width:132px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cstrong\u003eDefining question\u003c/strong\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"height:35px; width:132px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cstrong\u003eHigh (Strong)\u003c/strong\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"height:35px; width:132px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cstrong\u003eModerate\u003c/strong\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"height:35px; width:132px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cstrong\u003eLow (Weak)\u003c/strong\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"height:35px; width:111px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cstrong\u003eSupport for essentiality of KEs\u003c/strong\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"height:35px; width:132px\"\u003e\r\n\t\t\t\u003cp\u003eAre downstream KEs and/or the AO prevented if an upstream KE is blocked?\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"height:35px; width:132px\"\u003e\r\n\t\t\t\u003cp\u003eDirect evidence from\u003cbr /\u003e\r\n\t\t\tspecifically designed\u003cbr /\u003e\r\n\t\t\texperimental studies\u003cbr /\u003e\r\n\t\t\tillustrating essentiality for at least one of the\u003cbr /\u003e\r\n\t\t\timportant KEs\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"height:35px; width:132px\"\u003e\r\n\t\t\t\u003cp\u003eIndirect evidence that sufficient modification of an expected modulating factor attenuates or\u003cbr /\u003e\r\n\t\t\taugments a KE\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"height:35px; width:132px\"\u003e\r\n\t\t\t\u003cp\u003eNo or contradictory\u003cbr /\u003e\r\n\t\t\texperimental evidence\u003cbr /\u003e\r\n\t\t\tof the essentiality of any\u003cbr /\u003e\r\n\t\t\tof the KEs.\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"height:35px; width:111px\"\u003e\r\n\t\t\t\u003cp\u003eMIE1: Increase in reactive oxygen and nitrogen species (RONS)\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd colspan=\"4\" style=\"height:35px; width:528px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cstrong\u003e\u003cem\u003eEssentiality is High.\u003c/em\u003e\u003c/strong\u003e\u003cem\u003e The most significant support comes from the relatively large number of studies using antioxidants or other interventions to reduce RONS, which show a reduction in DNA damage and mutations. Additional support comes from experiments increasing external oxidants like H2O2, which show that RONS are independently capable of causing DNA damage and mutations. Uncertainties arise from the smaller effects of RONS on DNA damage compared with ionizing radiation. Mammary gland relevance is less certain due to the relatively few experiments in breast tissue.\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"height:100px; width:111px\"\u003e\r\n\t\t\t\u003cp\u003eMIE2: Increase in DNA damage\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd colspan=\"4\" style=\"height:100px; width:528px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cstrong\u003e\u003cem\u003eEssentiality is High.\u003c/em\u003e\u003c/strong\u003e\u003cem\u003e The essentiality of this MIE to cancer is generally accepted. Supporting evidence comes from application of mutagenic agents: the increase in DNA damage precedes mutations, proliferation, and tumorigenesis. Further indirect evidence comes from evidence for MIE1, in which antioxidants that reduce DNA damage also reduce mutations and chromosomal damage. Finally, mutations in DNA repair genes increase the risk of tumors.\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"height:100px; width:111px\"\u003e\r\n\t\t\t\u003cp\u003eKE1: Increase in mutation\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd colspan=\"4\" style=\"height:100px; width:528px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cstrong\u003e\u003cem\u003eEssentiality is High.\u003c/em\u003e\u003c/strong\u003e\u003cem\u003e The contribution of this MIE to cancer is generally accepted. Evidence comes from knock-out and knock-in experiments, which find that mutations in certain key genes increase tumorigenesis. However, an ongoing debate pits the singular importance of mutations against a significant role for the tissue microenvironment. This debate is fueled by transplant studies that show the importance of tissue environment for tumorigenesis and suggesting that mutations may not be sufficient for tumorigenesis.\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"height:100px; width:111px\"\u003e\r\n\t\t\t\u003cp\u003eKE2: Increase in proliferation\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd colspan=\"4\" style=\"height:100px; width:528px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cstrong\u003e\u003cem\u003eEssentiality is High.\u003c/em\u003e\u003c/strong\u003e\u003cem\u003e Evidence comes from transplant experiments showing that non-proliferating tissue is less tumorigenic than proliferating lesions, and from interventions that reduce both proliferation and tumors. Further evidence comes from animals that are resistant to both mammary gland proliferation and tumors from ionizing radiation. Uncertainty arises from conflicting evidence on the tumorigenicity of hyperplasia, the absence of hyperplasia observed before some tumors, and spontaneous regression of tumors.\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"height:100px; width:111px\"\u003e\r\n\t\t\t\u003cp\u003eKE3: Increase in inflammation\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd colspan=\"4\" style=\"height:100px; width:528px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cstrong\u003e\u003cem\u003eEssentiality is Moderate. \u003c/em\u003e\u003c/strong\u003e\u003cem\u003eEvidence comes from using genetic modifications, antibodies, and antioxidants to reduce inflammatory and anti-inflammatory factors. These interventions reduce DNA damage, mutations, and mechanisms contributing to tumorigenesis and invasion. Uncertainty arises from conflicting effects in different genetic backgrounds and in different organs.\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\u003c/tbody\u003e\r\n\u003c/table\u003e\r\n\r\n\u003cp style=\"margin-left:.5in\"\u003e\u003ca name=\"_ENREF_1\"\u003eRusso, I. H. and J. Russo (1996). \u0026quot;Mammary gland neoplasia in long-term rodent studies.\u0026quot; \u003cu\u003eEnvironmental health perspectives\u003c/u\u003e \u003cstrong\u003e104\u003c/strong\u003e(9): 938-967\u003c/a\u003e\u003c/p\u003e\r\n","weight_of_evidence_summary":"\u003cp\u003eIR appears to be a \u0026ldquo;complete\u0026rdquo; carcinogen in the mammary gland in that the toxin acts as an initiator through the formation of oxidative stress and pro-mutagenic DNA damage and (the MIEs) and as a promoter through increasing inflammation and proliferation, similar to many chemical carcinogens (Russo and Russo 1996). We have high confidence in the evidence linking stressor (IR) with adverse outcome (breast cancer). \u0026nbsp;The weight of evidence for the first pathway from RONS and DNA damage to Mutation and Proliferation is High while the weight of evidence for the second pathway from RONS to Inflammation to Proliferation and Breast Cancer is Moderate. These evaluations are based on the supporting evidence for all KEs and the considerations in Annex 1, and based on the need for additional evidence in the essentiality of Inflammation for the genesis of breast cancer.\u003c/p\u003e\r\n\r\n\u003cp\u003eThis AOP could not address the large number of related topics that interact with the key events described here. These topics include events following IR that may interact with these key events such as immune surveillance (which may change with the inflammatory environment after IR (Schreiber, Old et al. 2011; Barcellos-Hoff 2013; Lumniczky and Safrany 2015); IR effect on survival/apoptosis and interactions of apoptosis with inflammation, mutation, compensatory proliferation, and selection process; changes to DNA repair; and the role of epigenetics in carcinogenesis from IR (Daino, Nishimura et al. 2018). This AOP also does not address other influences on these key events beyond reproductive hormones and typical breast development. Subsequent contributions to this AOP should elaborate on these points.\u003c/p\u003e\r\n\r\n\u003ctable border=\"1\" cellpadding=\"0\" cellspacing=\"0\"\u003e\r\n\t\u003ctbody\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"height:11px; width:150px\"\u003e\r\n\t\t\t\u003cp\u003e\u0026nbsp;\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd colspan=\"2\" style=\"height:11px; width:125px\"\u003e\r\n\t\t\t\u003cp\u003e\u0026nbsp;\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd colspan=\"2\" style=\"height:11px; width:119px\"\u003e\r\n\t\t\t\u003cp\u003e\u0026nbsp;\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"height:11px; width:118px\"\u003e\r\n\t\t\t\u003cp\u003e\u0026nbsp;\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"height:11px; width:126px\"\u003e\r\n\t\t\t\u003cp\u003e\u0026nbsp;\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"height:20px; width:150px\"\u003e\r\n\t\t\t\u003cp\u003e\u0026nbsp;\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd colspan=\"2\" style=\"height:20px; width:125px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cstrong\u003eDefining question\u003c/strong\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd colspan=\"2\" style=\"height:20px; width:119px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cstrong\u003eHigh (Strong)\u003c/strong\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"height:20px; width:118px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cstrong\u003eModerate\u003c/strong\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"height:20px; width:126px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cstrong\u003eLow (Weak)\u003c/strong\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"height:79px; width:150px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cstrong\u003e2. Support for essentiality of KEs\u003c/strong\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd colspan=\"2\" style=\"height:79px; width:125px\"\u003e\r\n\t\t\t\u003cp\u003eAre downstream KEs and/or the AO prevented if an upstream KE is blocked?\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd colspan=\"2\" style=\"height:79px; width:119px\"\u003e\r\n\t\t\t\u003cp\u003eDirect evidence from\u003cbr /\u003e\r\n\t\t\tspecifically designed\u003cbr /\u003e\r\n\t\t\texperimental studies\u003cbr /\u003e\r\n\t\t\tillustrating essentiality for at least one of the\u003cbr /\u003e\r\n\t\t\timportant KEs\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"height:79px; width:118px\"\u003e\r\n\t\t\t\u003cp\u003eIndirect evidence that sufficient modification of an expected modulating factor attenuates or\u003cbr /\u003e\r\n\t\t\taugments a KE\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"height:79px; width:126px\"\u003e\r\n\t\t\t\u003cp\u003eNo or contradictory\u003cbr /\u003e\r\n\t\t\texperimental evidence\u003cbr /\u003e\r\n\t\t\tof the essentiality of any\u003cbr /\u003e\r\n\t\t\tof the KEs.\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"height:79px; width:150px\"\u003e\r\n\t\t\t\u003cp\u003eMIE: Increase in DNA damage\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd colspan=\"6\" style=\"height:79px; width:488px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cstrong\u003e\u003cem\u003eEssentiality is High.\u003c/em\u003e\u003c/strong\u003e\u003cem\u003e The essentiality of this MIE to cancer is generally accepted. Supporting evidence comes from application of mutagenic agents: the increase in DNA damage precedes mutations, proliferation, and tumorigenesis. Further indirect evidence comes from evidence for MIE1, in which antioxidants that reduce DNA damage also reduce mutations and chromosomal damage. Finally, mutations in DNA repair genes increase the risk of tumors.\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"height:79px; width:150px\"\u003e\r\n\t\t\t\u003cp\u003eKE/AO: Increase in mutation\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd colspan=\"6\" style=\"height:79px; width:488px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cstrong\u003e\u003cem\u003eEssentiality is High.\u003c/em\u003e\u003c/strong\u003e\u003cem\u003e The contribution of this MIE to cancer is generally accepted. Evidence comes from knock-out and knock-in experiments, which find that mutations in certain key genes increase tumorigenesis. However, an ongoing debate pits the singular importance of mutations against a significant role for the tissue microenvironment. This debate is fueled by transplant studies that show the importance of tissue environment for tumorigenesis and suggesting that mutations may not be sufficient for tumorigenesis.\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"height:79px; width:150px\"\u003e\r\n\t\t\t\u003cp\u003eKE: Increase, Cell Proliferation (epithelial cells)\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd colspan=\"6\" style=\"height:79px; width:488px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cstrong\u003e\u003cem\u003eEssentiality is High. \u003c/em\u003e\u003c/strong\u003e\u003cem\u003eCellular proliferation is a key characteristic of cancer cells and can lead to hyperplasia, an intermediate phase in the development of tumorigenesis.\u003c/em\u003e\u003cem\u003e Proliferation also increases the number of cells with mutations, which can further promote proliferation and/or changes to the local microenvironment.\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"height:79px; width:150px\"\u003e\r\n\t\t\t\u003cp\u003eKE/AO: Increase, Ductal Hyperplasia\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd colspan=\"6\" style=\"height:79px; width:488px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cstrong\u003e\u003cem\u003eEssentiality is High.\u003c/em\u003e\u003c/strong\u003e\u003cem\u003e Evidence comes from transplant experiments showing that non-proliferating tissue is less tumorigenic than proliferating lesions, and from interventions that reduce both proliferation and tumors. Further evidence comes from animals that are resistant to both mammary gland proliferation and tumors from ionizing radiation. Uncertainty arises from conflicting evidence on the tumorigenicity of hyperplasia, the absence of hyperplasia observed before some tumors, and spontaneous regression of tumors.\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"height:79px; width:150px\"\u003e\r\n\t\t\t\u003cp\u003eKEs: Tissue Resident Cell Activation, Increased Pro-inflammatory mediators, Leukocyte recruitment/activation\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd colspan=\"6\" style=\"height:79px; width:488px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cstrong\u003e\u003cem\u003eEssentiality is Moderate. \u003c/em\u003e\u003c/strong\u003e\u003cem\u003eThese key events were reviewed as a group. Evidence comes from using genetic modifications, antibodies, and antioxidants to reduce inflammatory and anti-inflammatory factors. These interventions reduce DNA damage, mutations, and mechanisms contributing to tumorigenesis and invasion. Uncertainty arises from conflicting effects in different genetic backgrounds and in different organs.\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"height:79px; width:150px\"\u003e\r\n\t\t\t\u003cp\u003eKE: Increase in reactive oxygen and nitrogen species (RONS)\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd colspan=\"6\" style=\"height:79px; width:488px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cstrong\u003e\u003cem\u003eEssentiality is High.\u003c/em\u003e\u003c/strong\u003e\u003cem\u003e The most significant support comes from the relatively large number of studies using antioxidants or other interventions to reduce RONS, which show a reduction in DNA damage and mutations. Additional support comes from experiments increasing external oxidants like H2O2, which show that RONS are independently capable of causing DNA damage and mutations. Uncertainties arise from the smaller effects of RONS on DNA damage compared with ionizing radiation. Mammary gland relevance is less certain due to the relatively few experiments in breast tissue.\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"height:11px; width:150px\"\u003e\r\n\t\t\t\u003cp\u003e\u0026nbsp;\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd colspan=\"2\" style=\"height:11px; width:125px\"\u003e\r\n\t\t\t\u003cp\u003e\u0026nbsp;\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd colspan=\"2\" style=\"height:11px; width:119px\"\u003e\r\n\t\t\t\u003cp\u003e\u0026nbsp;\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"height:11px; width:118px\"\u003e\r\n\t\t\t\u003cp\u003e\u0026nbsp;\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"height:11px; width:126px\"\u003e\r\n\t\t\t\u003cp\u003e\u0026nbsp;\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"height:20px; width:150px\"\u003e\r\n\t\t\t\u003cp\u003e\u0026nbsp;\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd colspan=\"2\" style=\"height:20px; width:125px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cstrong\u003eDefining question\u003c/strong\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd colspan=\"2\" style=\"height:20px; width:119px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cstrong\u003eHigh (Strong)\u003c/strong\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"height:20px; width:118px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cstrong\u003eModerate\u003c/strong\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"height:20px; width:126px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cstrong\u003eLow (Weak)\u003c/strong\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"height:76px; width:150px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cstrong\u003e1. Support for biological plausibility of KERs\u003c/strong\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd colspan=\"2\" style=\"height:76px; width:125px\"\u003e\r\n\t\t\t\u003cp\u003ea. Is there a mechanistic relationship between KEup and KEdown consistent with established biological knowledge?\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd colspan=\"2\" style=\"height:76px; width:119px\"\u003e\r\n\t\t\t\u003cp\u003eExtensive understanding of the KER based on extensive previous documentation and broad acceptance\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"height:76px; width:118px\"\u003e\r\n\t\t\t\u003cp\u003eKER is plausible based on analogy to accepted\u003cbr /\u003e\r\n\t\t\tbiological relationships, but scientific understanding is incomplete\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"height:76px; width:126px\"\u003e\r\n\t\t\t\u003cp\u003eEmpirical support for\u003cbr /\u003e\r\n\t\t\tassociation between KEs, but the structural or functional\u003cbr /\u003e\r\n\t\t\trelationship between them is not understood.\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"height:40px; width:150px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cem\u003eMIE DNA damage leads to Increase in Mutations (intermediate AO)\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; \u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd colspan=\"6\" style=\"height:40px; width:488px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cstrong\u003e\u003cem\u003eHigh. \u003c/em\u003e\u003c/strong\u003e\u003cem\u003eDNA damage in the form of nucleotide damage, single strand and double strand breaks, and complex damage can generate mutations, particularly when a damaged cell undergoes replication.\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"height:40px; width:150px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cem\u003eIncrease in Mutations leads to \u003c/em\u003e\u003cem\u003eIncrease, Cell Proliferation (epithelial cells)\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd colspan=\"6\" style=\"height:40px; width:488px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cstrong\u003e\u003cem\u003eHigh. \u003c/em\u003e\u003c/strong\u003e\u003cem\u003eMultiple mechanisms limit the proliferation of cells in normal biological systems. Mutations in many of the genes controlling these mechanisms promote proliferation.\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"height:40px; width:150px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cem\u003eIncrease, Cell Proliferation (epithelial cells) leads to Increase in Mutation\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd colspan=\"6\" style=\"height:40px; width:488px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cstrong\u003e\u003cem\u003eHigh. \u003c/em\u003e\u003c/strong\u003e\u003cem\u003eBiological plausibility is high since proliferation is generally acknowledged to increase mutations through incorporating or amplifying the impact of unrepaired DNA damage as mutations.\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"height:40px; width:150px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cem\u003eIncrease, Cell Proliferation (epithelial cells) leads to Increase, Ductal Hyperplasia (intermediate AO)\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd colspan=\"6\" style=\"height:40px; width:488px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cstrong\u003e\u003cem\u003eNot Specified. \u003c/em\u003e\u003c/strong\u003e\u003cem\u003eThis relationship is generally accepted, but evidence has not been compiled for this AOP.\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"height:40px; width:150px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cem\u003eIncrease, Ductal Hyperplasia increases risk of Breast Cancer (AO)\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd colspan=\"6\" style=\"height:40px; width:488px\"\u003e\r\n\t\t\t\u003cp\u003e\u0026nbsp;\u003cstrong\u003e\u003cem\u003eHigh.\u003c/em\u003e\u003c/strong\u003e \u003cem\u003eIt is generally accepted that proliferation and hyperplasia increase the risk of breast cancer.\u003c/em\u003e\u003cem\u003e Evidence comes from transplant experiments showing that non-proliferating tissue is less tumorigenic than proliferating lesions, and from interventions that reduce both lesions and tumors. Further evidence comes from animals that are resistant to both mammary gland hyperplasia and tumors from ionizing radiation. Uncertainty arises from conflicting evidence on the tumorigenicity of hyperplasia, the absence of hyperplasia observed before some tumors, and spontaneous regression of tumors.\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"height:40px; width:150px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cem\u003eIncrease in DNA damage leads to Tissue resident cell activation\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd colspan=\"6\" style=\"height:40px; width:488px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cstrong\u003e\u003cem\u003eHigh. \u003c/em\u003e\u003c/strong\u003e\u003cem\u003eBiological plausibility is high since DNA damage generates inflammatory signals (DAMPS).\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"height:40px; width:150px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cem\u003eTissue resident cell activation leads to Increase in Pro-inflammatory mediators\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd colspan=\"6\" style=\"height:40px; width:488px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cstrong\u003e\u003cem\u003eHigh. \u003c/em\u003e\u003c/strong\u003e\u003cem\u003eThis relationship is well established.\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"height:40px; width:150px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cem\u003ePro-inflammatory mediators lead to Leukocyte recruitment/activation\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd colspan=\"6\" style=\"height:40px; width:488px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cstrong\u003e\u003cem\u003eHigh. \u003c/em\u003e\u003c/strong\u003e\u003cem\u003eThis relationship is well established.\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"height:40px; width:150px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cem\u003ePro-inflammatory mediators, Laukocyte recruitment/ activation lead to an Increase in RONS\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd colspan=\"6\" style=\"height:40px; width:488px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cstrong\u003e\u003cem\u003eHigh.\u003c/em\u003e\u003c/strong\u003e\u003cem\u003e Inflammation is commonly understood to generate RONS via inflammatory signaling and activated immune cells.\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"height:40px; width:150px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cem\u003eIncrease in RONS leads to Increase in DNA damage (intermediate AO)\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd colspan=\"6\" style=\"height:40px; width:488px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cstrong\u003e\u003cem\u003eHigh.\u003c/em\u003e\u003c/strong\u003e \u003cem\u003eReactive oxygen and nitrogen species from oxygen and respiratory activity are generally acknowledged to damage DNA under a range of cellular conditions.\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"height:40px; width:150px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cem\u003eIncrease in RONS leads to Tissue resident cell activation\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd colspan=\"6\" style=\"height:40px; width:488px\"\u003e\r\n\t\t\t\u003cp\u003e\u0026nbsp;\u003cstrong\u003e\u003cem\u003eModerate. \u003c/em\u003e\u003c/strong\u003e\u003cem\u003eDamage from RONS can activate some inflammatory and anti-inflammatory pathways (TLR, TGF-\u0026beta;), and RONS are an essential part of the primary signaling pathways of multiple inflammatory and anti-inflammatory pathways (TLR4, TNF\u003c/em\u003e-a\u003cem\u003e, TGF-\u0026beta;, NFkB). \u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"height:40px; width:150px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cem\u003ePro-inflammatory mediators lead to Increase, Cell Proliferation (epithelial cells) \u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd colspan=\"6\" style=\"height:40px; width:488px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cstrong\u003e\u003cem\u003eHigh. \u003c/em\u003e\u003c/strong\u003e\u003cem\u003eInflammation is generally understood to lead to proliferation during recovery from inflammation.\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"height:40px; width:150px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cem\u003ePro-inflammatory mediators promote Breast Cancer\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd colspan=\"6\" style=\"height:40px; width:488px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cstrong\u003e\u003cem\u003eModerate.\u003c/em\u003e\u003c/strong\u003e\u003cem\u003e Tissue environment is known to be a major factor in carcinogenesis, and inflammatory processes are implicated in the development and invasiveness of breast and other cancers.\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"height:12px; width:150px\"\u003e\r\n\t\t\t\u003cp\u003e\u0026nbsp;\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"height:12px; width:112px\"\u003e\r\n\t\t\t\u003cp\u003e\u0026nbsp;\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd colspan=\"2\" style=\"height:12px; width:125px\"\u003e\r\n\t\t\t\u003cp\u003e\u0026nbsp;\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd colspan=\"2\" style=\"height:12px; width:125px\"\u003e\r\n\t\t\t\u003cp\u003e\u0026nbsp;\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"height:12px; width:126px\"\u003e\r\n\t\t\t\u003cp\u003e\u0026nbsp;\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"height:20px; width:150px\"\u003e\r\n\t\t\t\u003cp\u003e\u0026nbsp;\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"height:20px; width:112px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cstrong\u003eDefining questions\u003c/strong\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd colspan=\"2\" style=\"height:20px; width:125px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cstrong\u003eHigh (Strong)\u003c/strong\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd colspan=\"2\" style=\"height:20px; width:125px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cstrong\u003eModerate\u003c/strong\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"height:20px; width:126px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cstrong\u003eLow (Weak)\u003c/strong\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"height:131px; width:150px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cstrong\u003e3. Empirical support for KERs\u003c/strong\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"height:131px; width:112px\"\u003e\r\n\t\t\t\u003cp\u003eDoes empirical evidence support that a change in KEup leads to an appropriate change in KEdown? Does KEup occur at lower doses and earlier time points than KE down and is the incidence of KEup \u0026gt; than that for KEdown? Inconsistencies?\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd colspan=\"2\" style=\"height:131px; width:125px\"\u003e\r\n\t\t\t\u003cp\u003eMultiple studies\u003cbr /\u003e\r\n\t\t\tshowing dependent\u003cbr /\u003e\r\n\t\t\tchange in both events\u003cbr /\u003e\r\n\t\t\tfollowing exposure to\u003cbr /\u003e\r\n\t\t\ta wide range of specific stressors. No or few critical data gaps or conflicting data\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd colspan=\"2\" style=\"height:131px; width:125px\"\u003e\r\n\t\t\t\u003cp\u003eDemonstrated dependent change in both events following exposure to a small number of stressors. Some inconsistencies\u003cbr /\u003e\r\n\t\t\twith expected pattern that can be explained by\u003cbr /\u003e\r\n\t\t\tvarious factors.\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"height:131px; width:126px\"\u003e\r\n\t\t\t\u003cp\u003eLimited or no studies\u003cbr /\u003e\r\n\t\t\treporting dependent\u003cbr /\u003e\r\n\t\t\tchange in both events\u003cbr /\u003e\r\n\t\t\tfollowing exposure to a\u003cbr /\u003e\r\n\t\t\tspecific stressor; and/or\u003cbr /\u003e\r\n\t\t\tsignificant inconsistencies in empirical support across taxa and species\u003cbr /\u003e\r\n\t\t\tthat don\u0026rsquo;t align with\u003cbr /\u003e\r\n\t\t\thypothesized AOP\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"height:40px; width:150px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cem\u003eMIE DNA damage leads to Increase in Mutations (intermediate AO)\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; \u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd colspan=\"6\" style=\"height:40px; width:488px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cstrong\u003e\u003cem\u003eHigh.\u003c/em\u003e\u003c/strong\u003e\u003cem\u003e It is generally accepted that DNA damage leads to mutations. Empirical support comes in part from the observation that agents which increase DNA damage also cause mutations, that DNA damage precedes the appearance of mutations, and that interventions to reduce DNA damage also reduce mutations. \u003c/em\u003e\u003cem\u003eNone of the identified studies measure both outcomes over the same range of time points. This constitutes a readily addressable data gap.\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"height:40px; width:150px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cem\u003eIncrease in Mutations leads to \u003c/em\u003e\u003cem\u003eIncrease, Cell Proliferation (epithelial cells)\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd colspan=\"6\" style=\"height:40px; width:488px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cstrong\u003e\u003cem\u003eModerate. \u003c/em\u003e\u003c/strong\u003e\u003cem\u003eMutations that promote \u003ca name=\"Prolif_AOPassessment\"\u003eproliferation\u003c/a\u003e are frequently found in cancers, and both mutation and proliferation occur in response to tumorigenic stressors like ionizing radiation. Although not measured together after stressors, mutations appear over the same time frame or prior to the appearance of proliferation. Multiple uncertainties and conflicting evidence weaken this key event relationship. The two key events differ in their dose response- mutation but not proliferation increases with ionizing radiation dose. Furthermore, a single mutation is not necessarily sufficient to increase proliferation- proliferation typically requires multiple mutations or a change in the surrounding environment. In mammary tissue, \u003c/em\u003e\u003cem\u003estromal state strongly influences the proliferative nature of epithelial cells \u0026ndash; even epithelial cells with mutated tumor suppressors may be unable to form tumors in the absence of stromal changes.\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"height:40px; width:150px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cem\u003eIncrease, Cell Proliferation (epithelial cells) leads to Increase in Mutation\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd colspan=\"6\" style=\"height:40px; width:488px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cstrong\u003e\u003cem\u003eHigh.\u003c/em\u003e\u003c/strong\u003e \u003cem\u003eWe did not evaluate the empirical support for this KER in response to IR. However \u003c/em\u003e\u003cem\u003eproliferation or mitosis is required for some types of DNA damage to be made permanent and heritable, and further DNA damage including mutation promoting double strand breaks can occur when cells divide before DNA repair is complete.\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"height:40px; width:150px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cem\u003eIncrease, Cell Proliferation (epithelial cells) leads to Increase, Ductal Hyperplasia (intermediate AO)\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd colspan=\"6\" style=\"height:40px; width:488px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cstrong\u003e\u003cem\u003eNot specified. \u003c/em\u003e\u003c/strong\u003e\u003cem\u003eThis relationship is generally accepted, but evidence has not been compiled for this AOP.\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"height:40px; width:150px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cem\u003eIncrease, Ductal Hyperplasia increases risk of Breast Cancer (AO)\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd colspan=\"6\" style=\"height:40px; width:488px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cstrong\u003e\u003cem\u003eHigh.\u003c/em\u003e\u003c/strong\u003e\u003cem\u003e Carcinogenic agents increase proliferation and hyperplasia as well as tumors. Proliferation and hyperplasia appear prior to or at the same time as tumors, grow into carcinomas, and form mammary tumors more effectively than non-proliferating tissue. Disruption of proliferation is associated with decreased tumor growth, and tumor resistant rats do not show proliferation. \u003c/em\u003e\u003cem\u003eHowever, the discrepancy between the non-linear proliferative and linear mammary tumor response to carcinogen dose coupled with evidence of independent occurrences of proliferation and tumorigenesis suggests that while proliferation and hyperplasia likely promote carcinogenesis, additional factors also contribute to carcinogenesis.\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"height:40px; width:150px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cem\u003eIncrease in DNA damage leads to Tissue resident cell activation\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd colspan=\"6\" style=\"height:40px; width:488px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cstrong\u003e\u003cem\u003eNot Specified. \u003c/em\u003e\u003c/strong\u003e\u003cem\u003eBiological plausibility is high since DNA damage generates inflammatory signals (DAMPS), but evidence has not been compiled for this AOP.\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"height:40px; width:150px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cem\u003eTissue resident cell activation leads to Increase in Pro-inflammatory mediators\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd colspan=\"6\" style=\"height:40px; width:488px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cstrong\u003e\u003cem\u003eNot specified. \u003c/em\u003e\u003c/strong\u003e\u003cem\u003eThis relationship is generally accepted, but empirical evidence has not been compiled for this KER in mammary gland.\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"height:40px; width:150px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cem\u003ePro-inflammatory mediators lead to Leukocyte recruitment/activation\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd colspan=\"6\" style=\"height:40px; width:488px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cstrong\u003e\u003cem\u003eNot specified. \u003c/em\u003e\u003c/strong\u003e\u003cem\u003eThis relationship is generally accepted, but evidence has not been compiled for this KER in mammary gland.\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"height:40px; width:150px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cem\u003eIncrease in Pro-inflammatory mediators and Leukocyte recruitment/ activation leads to an Increase in RONS lead to an Increase in RONS\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd colspan=\"6\" style=\"height:40px; width:488px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cstrong\u003e\u003cem\u003eHigh.\u003c/em\u003e\u003c/strong\u003e\u003cem\u003e Signals arising from inflammation can be both pro- and anti-inflammatory, and both can have effects on RONS and downstream key events. Multiple inflammation-related factors increase RONS or oxidative damage, and ionizing radiation increases both inflammation-related signaling and RONS or oxidative damage over the same time points. Interventions to reduce inflammation also reduce RONS. The dose-dependence of the response to stressors is generally consistent between the two key events, although this is based on a small number of studies with some conflicting evidence.\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"height:40px; width:150px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cem\u003e\u0026nbsp;Increase in RONS leads to Increase in DNA damage (intermediate AO)\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd colspan=\"6\" style=\"height:40px; width:488px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cstrong\u003e\u003cem\u003eHigh.\u003c/em\u003e\u003c/strong\u003e\u003cem\u003e Multiple studies show an increase in DNA damage with RONS treatment as well as dependent changes in both RONS and DNA damage in response to stressors. DNA damage increases with RONS dose, \u003c/em\u003e\u003cem\u003eand temporal concordance between RONS and DNA damage events following ionizing radiation is consistent with a causative relationship, although few studies examine multiple doses and time points. A small number of studies do not find double strand breaks at physiological doses, or report an increase in one key event but not the other.\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"height:40px; width:150px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cem\u003eIncrease in RONS leads to Tissue resident cell activation\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd colspan=\"6\" style=\"height:40px; width:488px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cstrong\u003e\u003cem\u003eModerate. \u003c/em\u003e\u003c/strong\u003e\u003cem\u003eBoth RONS and inflammation increase in response to agents that increase either RONS or inflammation. Multiple studies show dose-dependent changes in both RONS and inflammation in response to stressors including ionizing radiation and antioxidants. RONS have been measured at the same or earlier time points as inflammatory markers, but additional studies are needed to characterize the inflammatory response at the earliest time points to support causation. Uncertainties come from the positive feedback from inflammation to RONS potentially interfering with attempts to establish causality, and from the large number of inflammation related factors with differing responses to stressors and experimental variation.\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"height:40px; width:150px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cem\u003ePro-inflammatory mediators lead to Increase, Cell Proliferation (epithelial cells) \u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd colspan=\"6\" style=\"height:40px; width:488px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cstrong\u003e\u003cem\u003eNot Specified. \u003c/em\u003e\u003c/strong\u003e\u003cem\u003eWe did not evaluate the empirical support for this KER in response to IR. However, inflammation is generally understood to promote proliferation and survival\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"height:40px; width:150px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cem\u003ePro-inflammatory mediators promote Breast Cancer\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd colspan=\"6\" style=\"height:40px; width:488px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cstrong\u003e\u003cem\u003eModerate.\u003c/em\u003e\u003c/strong\u003e\u003cem\u003e Interventions to increase inflammatory factors increase the carcinogenic potential of targeted and non-targeted cells. Inflammation is documented at earlier time points than tumorigenesis or invasion- within minutes or hours compared to days to months for carcinogenesis, consistent with an inflammatory mechanism of tumorigenesis and invasion. Inhibition of cytokines, inflammatory signaling pathways, and downstream effectors of inflammation activity prevent transformation, tumorigenesis, and invasion following IR or stimulation of inflammatory pathways. However, the key event and the adverse outcome differ in their dose-response to ionizing radiation: inflammation always does not increase linearly with dose, while breast cancer and invasion does. Uncertainty arises from the multifunctional nature of inflammation-related pathways which may be pro- or anti-inflammatory and pro- or anti-carcinogenic based on context. Both pro- and anti-inflammatory factors may contribute to carcinogenesis- further research will be required to identify the context of each. \u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd\u003e\u0026nbsp;\u003c/td\u003e\r\n\t\t\t\u003ctd\u003e\u0026nbsp;\u003c/td\u003e\r\n\t\t\t\u003ctd\u003e\u0026nbsp;\u003c/td\u003e\r\n\t\t\t\u003ctd\u003e\u0026nbsp;\u003c/td\u003e\r\n\t\t\t\u003ctd\u003e\u0026nbsp;\u003c/td\u003e\r\n\t\t\t\u003ctd\u003e\u0026nbsp;\u003c/td\u003e\r\n\t\t\t\u003ctd\u003e\u0026nbsp;\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\u003c/tbody\u003e\r\n\u003c/table\u003e\r\n\r\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\r\n\r\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\r\n\r\n\u003cp\u003eSupporting Information for Essentiality Call to be Included in Annex 1:\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003cstrong\u003eOverall assessment of KEs \u003c/strong\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003eIR appears to be a \u0026ldquo;complete\u0026rdquo; carcinogen in the mammary gland in that the stressor acts as an initiator through the formation of oxidative stress and pro-mutagenic DNA damage and (the MIEs) and as a promoter through increasing inflammation and proliferation, similar to many chemical carcinogens (Russo and Russo 1996). We have high confidence in the evidence linking stressor (IR) with adverse outcome (breast cancer). \u0026nbsp;The weight of evidence for the first pathway from RONS to DNA damage, Mutation, and Proliferation is High while the weight of evidence for the second pathway from RONS to Inflammation to Proliferation and Breast Cancer is Moderate. These evaluations are based on the supporting evidence for all KEs and the considerations in Annex 1, and based on the need for additional evidence in the essentiality of Inflammation for the genesis of breast cancer.\u003c/p\u003e\r\n\r\n\u003ch2\u003eMIE: Increase in DNA damage\u003c/h2\u003e\r\n\r\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eEssentiality is High.\u003c/em\u003e\u003c/strong\u003e\u003cem\u003e The essentiality of this MIE to cancer is generally accepted. Supporting evidence comes from application of mutagenic agents: the increase in DNA damage precedes mutations, proliferation, and tumorigenesis. Further indirect evidence comes from evidence for MIE1, in which antioxidants that reduce DNA damage also reduce mutations and chromosomal damage. Finally, mutations in DNA repair genes increase the risk of tumors.\u003c/em\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003eIncreases or decreases in DNA damage are associated with corresponding increases or decreases in downstream key events in the pathway to breast cancer. An external agent (ionizing radiation) that increases DNA damage (Padula, Ponzinibbio et al. 2016) also causes chromosomal damage and increased mutations (Sandhu and Birnboim 1997; Jones, Riggs et al. 2007; Denissova, Nasello et al. 2012; Fibach and Rachmilewitz 2015), transforms cells (Yang, Craise et al. 1992; Yang, Georgy et al. 1997; Unger, Wienberg et al. 2010), and causes tumors (Poirier and Beland 1994; Little 2009). Polymorphisms or mutations in DNA repair genes affect tumor formation after ionizing radiation in animals (Yu, Okayasu et al. 2001; Umesako, Fujisawa et al. 2005) and in people (Millikan, Player et al. 2005; Andrieu, Easton et al. 2006; Broeks, Braaf et al. 2007; Bernstein, Haile et al. 2010; Brooks, Teraoka et al. 2012; Pijpe, Andrieu et al. 2012; Bernstein, Thomas et al. 2013). Consistent with these findings, antioxidants that reduce DNA damage from stressors like IR also reduce chromosomal aberrations and micronuclei arising from those stressors (Azzam, De Toledo et al. 2002; Choi, Kang et al. 2007; Jones, Riggs et al. 2007).\u003c/p\u003e\r\n\r\n\u003ch3\u003e\u003ca name=\"_Toc2345655\"\u003eEvidence in mammary gland\u003c/a\u003e\u003c/h3\u003e\r\n\r\n\u003cp\u003eThe majority of research on the effects of IR on DNA damage has been performed in tissues other than mammary gland, but several studies suggest that effects in the mammary gland (and its consequences) would be consistent with other tissues. Oxidative DNA damage in mammary cells increases immediately after exposure to IR (Haegele, Wolfe et al. 1998), and double stranded breaks, micronuclei, and (later) chromosomal aberrations appear two hours to six days after IR exposure in vivo and in vitro (Soler, Pampalona et al. 2009; Snijders, Marchetti et al. 2012; Hernandez, Terradas et al. 2013). Genomic instability was reported in genetically susceptible cells after a month of higher doses of IR (4 doses of 1.8 Gy but not 0.75 Gy) (Snijders, Marchetti et al. 2012).\u003c/p\u003e\r\n\r\n\u003ch2\u003eKE/AO: Increase in mutation\u003c/h2\u003e\r\n\r\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eEssentiality is High.\u003c/em\u003e\u003c/strong\u003e\u003cem\u003e The contribution of this MIE to cancer is generally accepted. Evidence comes from knock-out and knock-in experiments, which find that mutations in certain key genes increase tumorigenesis. However, an ongoing debate pits the singular importance of mutations against a significant role for the tissue microenvironment. This debate is fueled by transplant studies that show the importance of tissue environment for tumorigenesis and suggesting that mutations may not be sufficient for tumorigenesis.\u003c/em\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003eMutations increase transformation in culture (Wang, Su et al. 2011) and \u003ca name=\"Prolif_KE1_Essentiality\"\u003eproliferation\u003c/a\u003e and tumors in mice (Radice, Ferreira-Cornwell et al. 1997; Umesako, Fujisawa et al. 2005; de Ostrovich, Lambertz et al. 2008; Podsypanina, Politi et al. 2008; Francis, Bergsied et al. 2009; Gustin, Karakas et al. 2009; Francis, Chakrabarti et al. 2011; Tao, Xiang et al. 2017). Restoring function in mutated genes regresses tumors in animals (Martins, Brown-Swigart et al. 2006; Podsypanina, Politi et al. 2008). Mutations are common in tumors (Haag, Hsu et al. 1996; Greenman, Stephens et al. 2007; Stratton, Campbell et al. 2009; CGAN (Cancer Genome Atlas Network) 2012; Vandin, Upfal et al. 2012; Garraway and Lander 2013; Vogelstein, Papadopoulos et al. 2013; Yang, Killian et al. 2015) and tumors are largely clonal, suggesting that individual mutations offer the tumor evolutionary advantages (Wang, Waters et al. 2014; Yates, Gerstung et al. 2015; Begg, Ostrovnaya et al. 2016).\u003c/p\u003e\r\n\r\n\u003ch3\u003e\u003ca name=\"_Toc2345660\"\u003eEvidence in mammary gland\u003c/a\u003e\u003c/h3\u003e\r\n\r\n\u003cp\u003eMany of the studies in support of the proliferative and tumorigenic role of mutations are in mammary gland or breast cancers. Further support for including DNA damage and mutation in the mechanistic pathway linking ionizing radiation with breast cancer comes from the observation that variants in DNA repair genes increase the risk of mammary tumors in animals after IR (Yu, Okayasu et al. 2001; Umesako, Fujisawa et al. 2005) and increase breast cancer after IR (Millikan, Player et al. 2005; Andrieu, Easton et al. 2006; Broeks, Braaf et al. 2007; Bernstein, Haile et al. 2010; Brooks, Teraoka et al. 2012; Pijpe, Andrieu et al. 2012; Bernstein, Thomas et al. 2013). BRCA is perhaps the best known DNA repair gene linked with breast cancer risk, and several studies of these studies have suggested a link between BRCA mutation status and increased susceptibility to breast cancer following ionizing radiation, particularly in women exposed at younger ages (Pijpe, Andrieu et al. 2012).\u003c/p\u003e\r\n\r\n\u003ch3\u003e\u003ca name=\"_Toc2345661\"\u003eUncertainties or Inconsistencies\u003c/a\u003e\u003c/h3\u003e\r\n\r\n\u003cp\u003eMutations alone are not sufficient or even essential for tumor growth in mammary glands. Mammary tumor incidence following ionizing radiation varies significantly by sex and depends on the presence of ovarian hormones (Cronkite, Shellabarger et al. 1960; Segaloff and Maxfield 1971; Shellabarger, Stone et al. 1976; Holtzman, Stone et al. 1979; Holtzman, Stone et al. 1981; Welsch, Goodrich-Smith et al. 1981; Clifton, Yasukawa-Barnes et al. 1985; Solleveld, van Zwieten et al. 1986; Broerse, Hennen et al. 1987; Lemon, Kumar et al. 1989; Inano, Suzuki et al. 1991; Inano, Suzuki et al. 1996; Peterson, Servinsky et al. 2005). Tumor growth from transplanted tumor cells varies with age, parity, and lactational status (Maffini, Calabro et al. 2005; McDaniel, Rumer et al. 2006), and stroma treated with carcinogens or IR supports tumors from pre-malignant epithelial cells (Barcellos-Hoff and Ravani 2000; Maffini, Soto et al. 2004; Nguyen, Oketch-Rabah et al. 2011). While the mechanisms underlying these contextual factors have not been clearly identified, the proliferative effect of hormones on the mammary gland may serve to amplify damaged and mutated cells and modify the stromal environment to increase the likelihood of cellular transformation. Inflammatory responses including the release of cytokines and the activation of inflammatory and anti-inflammatory signaling pathways likely also amplify the effects of DNA damage and mutations through many of the same mechanisms.\u003c/p\u003e\r\n\r\n\u003ch2\u003eKE: Increase in proliferation\u003c/h2\u003e\r\n\r\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eEssentiality is High. \u003c/em\u003e\u003c/strong\u003e\u003cem\u003eCellular proliferation is a key characteristic of cancer cells (Hanahan and Weinberg 2011) and can lead to hyperplasia, an intermediate phase in the development of tumorigenesis. \u003c/em\u003e\u003cem\u003eProliferation also increases the number of cells with mutations, which can further promote proliferation and/or changes to the local microenvironment.\u003c/em\u003e\u003c/p\u003e\r\n\r\n\u003ch3\u003e\u003ca name=\"_Toc2345669\"\u003eEvidence in mammary gland\u003c/a\u003e\u003c/h3\u003e\r\n\r\n\u003cp\u003eMultiple studies show that mammary gland proliferates after IR or chemical carcinogen treatment prior to the appearance of mammary tumors. Epithelial cells proliferate following IR in vitro (Mukhopadhyay, Costes et al. 2010) and in vivo (Nguyen, Oketch-Rabah et al. 2011; Snijders, Marchetti et al. 2012; Suman, Johnson et al. 2012; Tang, Fernandez-Garcia et al. 2014). Increasing proliferation leads to hyperplasia (Korkaya, Paulson et al. 2009). Proliferative nodules and \u003ca name=\"Prolif_KE2_Essentiality\"\u003ehyperplasia\u003c/a\u003e appear in mammary terminal end bud, alveolae, and ducts of rats and mice after exposure to chemical carcinogens (Beuving, Bern et al. 1967; Beuving, Faulkin et al. 1967; Russo, Saby et al. 1977; Purnell 1980) and ionizing radiation (Faulkin, Shellabarger et al. 1967; Ullrich and Preston 1991; Imaoka, Nishimura et al. 2006). Proliferating foci precede the development of tumors (Haslam and Bern 1977; Purnell 1980) and form tumors more effectively than non-proliferating tissue (Deome, Faulkin et al. 1959; Beuving 1968; Rivera, Hill et al. 1981).\u003c/p\u003e\r\n\r\n\u003cp\u003eSupporting the essentiality of these proliferative processes to tumorigenesis, ACI rats that exhibit no mammary proliferation or hyperplasia following IR are resistant to tumors following IR (Kutanzi, Koturbash et al. 2010). Interventions reducing proliferation in susceptible PyVT and BALB/c mice also reduce mammary tumors (Luo, Fan et al. 2009; Connelly, Barham et al. 2011; Tang, Fernandez-Garcia et al. 2014).\u003c/p\u003e\r\n\r\n\u003ch3\u003e\u003ca name=\"_Toc2345670\"\u003eUncertainties or Inconsistencies\u003c/a\u003e\u003c/h3\u003e\r\n\r\n\u003cp\u003eSome studies report carcinogenesis in the absence of hyperplasia (Sinha and Dao 1974) and others do not find increased tumorigenesis from transplanted hyperplasia (Beuving, Bern et al. 1967; Haslam and Bern 1977; Sinha and Dao 1977). The failure of some proliferative foci to form tumors and the regression of some tumors when formed (Haslam and Bern 1977; Purnell 1980; Korkola and Archer 1999) suggests that proliferation may not be sufficient for sustained tumorigenesis in mammary gland.\u003c/p\u003e\r\n\r\n\u003ch2\u003eKE/AO: Increase, ductal hyperplasia\u003c/h2\u003e\r\n\r\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eEssentiality is High.\u003c/em\u003e\u003c/strong\u003e\u003cem\u003e Evidence comes from transplant experiments showing that non-proliferating tissue is less tumorigenic than proliferating lesions, and from interventions that reduce both proliferation and tumors. Further evidence comes from animals that are resistant to both mammary gland proliferation and tumors from ionizing radiation. Uncertainty arises from conflicting evidence on the tumorigenicity of hyperplasia, the absence of hyperplasia observed before some tumors, and spontaneous regression of tumors.\u003c/em\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003eHyperplasia signals the presence of excess proliferation (a key characteristic of cancer cells (Hanahan and Weinberg 2011)) and represents an intermediate phase in the development of tumorigenesis.\u003c/p\u003e\r\n\r\n\u003ch3\u003eEvidence in mammary gland\u003c/h3\u003e\r\n\r\n\u003cp\u003eMultiple studies show that mammary gland proliferates after IR or chemical carcinogen treatment prior to the appearance of mammary tumors. Proliferative nodules and hyperplasia appear in mammary terminal end bud, alveolae, and ducts of rats and mice after exposure to chemical carcinogens (Beuving, Bern et al. 1967; Beuving, Faulkin et al. 1967; Russo, Saby et al. 1977; Purnell 1980) and ionizing radiation (Faulkin, Shellabarger et al. 1967; Ullrich and Preston 1991; Imaoka, Nishimura et al. 2006). Proliferating foci precede the development of tumors (Haslam and Bern 1977; Purnell 1980) and form tumors more effectively than non-proliferating tissue (Deome, Faulkin et al. 1959; Beuving 1968; Rivera, Hill et al. 1981). Adenocarcinomas in rats appear to preferentially form from terminal end bud hyperplasia (Haslam and Bern 1977; Russo, Saby et al. 1977; Purnell 1980), similar to the origin of many breast cancers for humans and for some mice after IR (Medina and Thompson 2000).\u003c/p\u003e\r\n\r\n\u003cp\u003eSupporting the essentiality of these proliferative processes to tumorigenesis, ACI rats that exhibit no mammary proliferation or hyperplasia following IR are resistant to tumors following IR (Kutanzi, Koturbash et al. 2010). Interventions reducing proliferation in susceptible PyVT and BALB/c mice also reduce mammary tumors (Luo, Fan et al. 2009; Connelly, Barham et al. 2011).\u003c/p\u003e\r\n\r\n\u003ch3\u003eUncertainties or Inconsistencies\u003c/h3\u003e\r\n\r\n\u003cp\u003eSome studies report carcinogenesis in the absence of hyperplasia (Sinha and Dao 1974) and others do not find increased tumorigenesis from transplanted hyperplasia (Beuving, Bern et al. 1967; Haslam and Bern 1977; Sinha and Dao 1977). The failure of some lesions to form tumors and the regression of some tumors when formed (Haslam and Bern 1977; Purnell 1980; Korkola and Archer 1999) suggests that hyperplasia alone may not be sufficient for sustained tumorigenesis in mammary gland.\u003c/p\u003e\r\n\r\n\u003ch2\u003e\u0026nbsp;\u003c/h2\u003e\r\n\r\n\u003ch2\u003eKEs: Tissue resident cell activation, Increase, Pro-inflammatory mediators, Leukocyte Recruitment/Activation\u003c/h2\u003e\r\n\r\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eEssentiality is Moderate. \u003c/em\u003e\u003c/strong\u003e\u003cem\u003eThese key events were reviewed as a group. Evidence comes from using genetic modifications, antibodies, and antioxidants to reduce inflammatory and anti-inflammatory factors. These interventions reduce DNA damage, mutations, and mechanisms contributing to tumorigenesis and invasion. Uncertainty arises from conflicting effects in different genetic backgrounds and in different organs.\u003c/em\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003eTumors and tumor cells exhibit features of inflammation, and inflammation is generally understood to promote transformation and tumor progression by supporting multiple hallmarks of cancer including oxidative activity and DNA damage, survival and proliferation, angiogenesis, and invasion and metastasis (Iliopoulos, Hirsch et al. 2009; Hanahan and Weinberg 2011; Esquivel-Velazquez, Ostoa-Saloma et al. 2015).\u003c/p\u003e\r\n\r\n\u003cp\u003eMany of these cancer promoting effects of inflammation can be seen following exposure to ionizing radiation (Bisht, Bradbury et al. 2003; Elahi, Suraweera et al. 2009; Nguyen, Oketch-Rabah et al. 2011; Bouchard, Bouvette et al. 2013; Nguyen, Fredlund et al. 2013; Illa-Bochaca, Ouyang et al. 2014). Inflammatory pathways are commonly activated in breast and mammary cancers following IR (Nguyen, Oketch-Rabah et al. 2011; Nguyen, Fredlund et al. 2013; Illa-Bochaca, Ouyang et al. 2014). Polymorphisms in inflammation genes are associated with breast cancer risk from IR in radiation technologists (Schonfeld, Bhatti et al. 2010) and with susceptibility to intestinal adenoma following IR in mice (Elahi, Suraweera et al. 2009). Cytokines TGF-\u0026beta; and IL6 transform\u0026nbsp; primary human mammospheres and pre-malignant mammary epithelial cell lines in vitro and make them tumorigenic in vivo (Sansone, Storci et al. 2007; Iliopoulos, Hirsch et al. 2009; Nguyen, Oketch-Rabah et al. 2011), and inflammation related factors COX2 and TGF-\u0026beta; are required for the full effect of IR on DNA damage and transformation in vitro and mammary tumor growth and invasion in vivo (Bisht, Bradbury et al. 2003; Nguyen, Oketch-Rabah et al. 2011).\u003c/p\u003e\r\n\r\n\u003cp\u003eOne mechanism of cancer promotion involves oxidative activity and DNA damage: inflammation in response to IR increases oxidative activity in a positive feedback loop leading to increased DNA lesions and mutations. Oxidative activity mediates the increase in inflammatory markers (TNF-a and neutrophil markers) in bladder and kidney (Ozyurt, Cevik et al. 2014), and TNF-a and neutrophils increase oxidative activity (Jackson, Gajewski et al. 1989; Stevens, Bucurenci et al. 1992; Zhang, Zhu et al. 2017). Inflammatory activity from neutrophils and TNF-a and NF-kB-dependent COX2 and NO damage DNA and increase mutations by increasing oxidative activity (Jackson, Gajewski et al. 1989; Zhou, Ivanov et al. 2005). The mutations can be reduced by blocking the inflammatory factors NF-kB, COX2, TNF-a, or nitric oxide, or with antioxidants (Jackson, Gajewski et al. 1989; Zhou, Ivanov et al. 2005; Zhou, Ivanov et al. 2008; Zhang, Zhu et al. 2017). Antibodies to TNF-a or TGF-\u0026beta; reduce DNA damage in bone marrow (Burr, Robinson et al. 2010; Rastogi, Coates et al. 2012) and CHO cells (Han, Chen et al. 2010). Inhibiting TNF-a also reduces genomic instability in directly irradiated (but not bystander) lymphocytes (Moore, Marsden et al. 2005) and in bone marrow of CBA/Ca mice susceptible to IR-induced leukemia but not resistant C57BL/6 mice (Lorimore, Mukherjee et al. 2011). Inhibiting inflammatory factors NF-kB or iNOS reduces IR-induced bystander mutations in lung fibroblasts (Zhou, Ivanov et al. 2008).\u003c/p\u003e\r\n\r\n\u003cp\u003eInflammatory pathways activated by IR are also capable of promoting tumor growth and metastasis. Exposure to IR or RONS sensitizes mammary epithelial cells to respond to TGF-\u0026beta; - which is widely activated by IR (Ehrhart, Segarini et al. 1997). IR and TGF-\u0026beta; signaling leads to an epithelial to mesenchymal (EMT)-like transition, which disrupts the expression and distribution of cell adhesion molecules and multicellular organization and promotes invasion (Park, Henshall-Powell et al. 2003; Andarawewa, Erickson et al. 2007; Andarawewa, Costes et al. 2011; Iizuka, Sasatani et al. 2017). This mechanism resembles wound healing (Koh and DiPietro 2011; Perez, Vago et al. 2014; Landen, Li et al. 2016), but also resembles malignancy - invasive breast cancer cell lines overexpress TGF-\u0026beta; and respond to TGF-\u0026beta; with increased invasion (Kim, Kim et al. 2004; Gomes, Terra et al. 2012).\u0026nbsp;\u003c/p\u003e\r\n\r\n\u003cp\u003eThe response to TGF-\u0026beta; likely involves an increase in senescence in fibroblasts. IR-induced senescence releases a suite of signaling molecules including pro-inflammatory IL6 and proteases (MMPs) (Tsai, Chuang et al. 2005; Liakou, Mavrogonatou et al. 2016; Perrott, Wiley et al. 2017). The signaling molecules released by IR-senescent fibroblasts promote the disorganized tissue structure of mammary epithelial cells and the growth, EMT, and invasion of breast cancer epithelial cells or mutant epithelial cells (Tsai, Chuang et al. 2005; Liakou, Mavrogonatou et al. 2016; Perrott, Wiley et al. 2017) and 3D mammary tumor models (Sourisseau, Harrington et al. 2011). The induction of senescence in fibroblasts by IR requires TGF-\u0026beta; (Liakou, Mavrogonatou et al. 2016), and the release of the pro-invasive signaling molecules involves an IL-1 dependent activation of NF-kB (Perrott, Wiley et al. 2017). Senescence following IR also selects for a post-senescent variant of epithelial cell that is more conducive to tumorigenesis (Mukhopadhyay, Costes et al. 2010).\u003c/p\u003e\r\n\r\n\u003cp\u003eIl6 may play an important function in the carcinogenic response to IR. IL6 is expressed in mouse mammary gland after IR (Bouchard, Bouvette et al. 2013). IL6 is produced by IR-senescent fibroblasts, but may also be expressed by epithelial cells after IR since primary human mammospheres and pre-malignant mammary epithelial cell lines respond to IL6 with increased IL6 expression (Sansone, Storci et al. 2007; Iliopoulos, Hirsch et al. 2009). IL6 promotes the mobility and tumorigenesis of normal and breast cancer epithelial cells (Sansone, Storci et al. 2007; Sasser, Sullivan et al. 2007; Studebaker, Storci et al. 2008; Iliopoulos, Hirsch et al. 2009; Iliopoulos, Jaeger et al. 2010). This activity depends on transcription factor NOTCH3, which supports the renewal of stem-like cell populations (Sansone, Storci et al. 2007), and NOTCH has been implicated in multiple other studies in the proliferative response to IR in mammary epithelia (Nguyen, Oketch-Rabah et al. 2011; Marusyk, Tabassum et al. 2014; Tang, Fernandez-Garcia et al. 2014). The NF-kB/IL6/STAT3 signaling pathway generates cancer stem cells in multiple types of breast cancer cells (Iliopoulos, Hirsch et al. 2009; Iliopoulos, Jaeger et al. 2010; Iliopoulos, Hirsch et al. 2011) and is also implicated in colon and other cancers (Iliopoulos, Jaeger et al. 2010). The inflammation related transcription factor NF-kB also contributes to mammary tumorigenesis and metastasis in PyVt mice, in which mammary tumors are induced by expression of an MMTV-driven oncogene (Connelly, Barham et al. 2011). Interestingly, breast cancer fibroblasts and fibroblasts from common sites of breast cancer metastasis (bone, lung) express IL6. IL6 is required for the growth and tumor promoting effects of these fibroblasts on ER-positive cancer cells in vitro and in vivo. ER-negative breast epithelial cells release autocrine IL6 and may therefore be less dependent on IL6 from fibroblasts, although IL6 also transforms these cells (Sasser, Sullivan et al. 2007; Studebaker, Storci et al. 2008; Iliopoulos, Hirsch et al. 2009).\u003c/p\u003e\r\n\r\n\u003cp\u003eInflammation is suspected to play a role in the indirect effects of radiation, in which cells not directly targeted by radiation exhibit effects including DNA damage and RONS (Lorimore and Wright 2003; Mukherjee, Coates et al. 2014; Sprung, Ivashkevich et al. 2015). In addition to the IR-induced release of inflammatory signals that are diffusible and can trigger systemic immune responses, inflammatory factors COX2 and TGF-\u0026beta; are produced in bystander cells that are not directly irradiated but are exposed to irradiated cells or media (Zhou, Ivanov et al. 2005; Zhou, Ivanov et al. 2008; Chai, Calaf et al. 2013; Chai, Lam et al. 2013; Wang, Wu et al. 2015).\u003c/p\u003e\r\n\r\n\u003cp\u003eInflammatory factors TGF-\u0026beta;, TNF-a, COX2, and NO are implicated in the RONS (Shao, Folkard et al. 2008; Zhou, Ivanov et al. 2008; Wang, Wu et al. 2015), DNA damage (Dickey, Baird et al. 2009; Han, Chen et al. 2010; Dickey, Baird et al. 2012; Chai, Calaf et al. 2013; Chai, Lam et al. 2013; Wang, Wu et al. 2015) and mutations (Zhou, Ivanov et al. 2005; Zhou, Ivanov et al. 2008) observed in bystander cells and in the appearance of genomic instability (Moore, Marsden et al. 2005; Natarajan, Gibbons et al. 2007; Lorimore, Chrystal et al. 2008; Lorimore, Mukherjee et al. 2011) after IR. Further evidence for inflammation in indirect effects of IR come from tumors arising from mammary epithelial cells transplanted into IR exposed cleared fat pads: inflammation-related genes and pathways are upregulated or enriched in the gene expression patters of these indirectly IR-induced tumors (Nguyen, Oketch-Rabah et al. 2011; Nguyen, Fredlund et al. 2013; Illa-Bochaca, Ouyang et al. 2014).\u003c/p\u003e\r\n\r\n\u003ch3\u003e\u003ca name=\"_Toc2345676\"\u003eEvidence in mammary gland\u003c/a\u003e\u003c/h3\u003e\r\n\r\n\u003cp\u003eMany of the studies above that link inflammatory signals with increased oxidative activity, senescence, EMT, bystander effects, genomic instability, and tumorigenesis, and metastasis use mammary tissue. Since inflammation-related signals are reported after IR in mammary gland (Barcellos-Hoff, Derynck et al. 1994; Dickey, Baird et al. 2009; Datta, Hyduke et al. 2012; Snijders, Marchetti et al. 2012; Bouchard, Bouvette et al. 2013; Wang, Wu et al. 2015) inflammation likely contributes to many of the effects of IR in this tissue.\u003c/p\u003e\r\n\r\n\u003ch3\u003e\u003ca name=\"_Toc2345677\"\u003eUncertainties or inconsistencies\u003c/a\u003e\u003c/h3\u003e\r\n\r\n\u003cp\u003eThe effects of inflammation can be both pro and anti-tumorigenic. For example, in addition to TGF-\u0026beta;\u0026rsquo;s role in EMT, in mammary epithelial cells TGF-\u0026beta; is essential to apoptosis of DNA damaged cells including damage following ionizing radiation (Ewan, Henshall-Powell et al. 2002), thus limiting genomic instability (Maxwell, Fleisch et al. 2008). Inflammatory factors TNF-a and COX2 play a similar role in bone marrow of C57BL/6 mice (Lorimore, Rastogi et al. 2013). By eliminating cells with severe DNA damage and curtailing genomic instability, apoptosis (and therefore TGF-\u0026beta; or TNF-a) limits the appearance of major (possibly carcinogenic) mutations following ionizing radiation. However, apoptosis (and thus TGF-\u0026beta; or TNF-a) can indirectly promote tumorigenesis through compensatory proliferation (Loree, Koturbash et al. 2006; Fogarty and Bergmann 2017).\u003c/p\u003e\r\n\r\n\u003cp\u003eGenetic background also influences the interaction between inflammation and tumorigenesis. Polymorphisms in inflammatory genes influence susceptibility to intestinal cancer following IR (Elahi, Suraweera et al. 2009). In the SPRET outbred mouse higher baseline TGF-\u0026beta; during development decreases tumor incidence following lower doses of IR (0.1 Gy), possibly by reducing ductal branching and susceptibility (Zhang, Lo et al. 2015). Conversely, the BALB/c mouse susceptible to mammary tumors after IR has a lower baseline TGF-\u0026beta; (and a polymorphism in a DNA damage repair-related gene). Early (4 hours) after low dose (0.075 Gy) IR BALB/c mice have suppressed immune pathways and macrophage response but increased IL6, COX2, and TGF-\u0026beta; pathway activation in mammary gland compared to the tumor-resistant C57BL/6 mouse (Snijders, Marchetti et al. 2012; Bouchard, Bouvette et al. 2013).\u0026nbsp; By 1 week after IR, the BALB/c mice show TGF-\u0026beta; -dependent inflammation in the mammary gland, and by 1 month after IR, their mammary glands show proliferation (Nguyen, Martinez-Ruiz et al. 2011; Snijders, Marchetti et al. 2012), suggesting that TGF-\u0026beta; is associated with inflammation, proliferation, and mammary tumorigenesis in these mice. Consistent with this pattern, BALB/c mice that are heterozygous for TGF-\u0026beta; are more resistant to mammary tumorigenesis following IR (Nguyen, Oketch-Rabah et al. 2011). However, the BALB/c mouse also has a polymorphism in a DNA repair gene associated with IR-induced genomic instability (Yu, Okayasu et al. 2001), making it difficult to distinguish potentially overlapping mechanisms.\u003c/p\u003e\r\n\r\n\u003cp\u003eWhile inflammatory signals are associated with bystander effects including DNA damage, genomic instability, and mutation, these effects vary between organs in vivo (Chai, Calaf et al. 2013; Chai, Lam et al. 2013), by genotype (Coates, Rundle et al. 2008; Lorimore, Chrystal et al. 2008; Lorimore, Mukherjee et al. 2011), and by cell type (Chai, Calaf et al. 2013). Further research will be required to identify all the underlying factors determining differences in bystander effects, but one variable is the appearance of a protective apoptotic response to cytokines under some conditions (Lorimore, Mukherjee et al. 2011; Lorimore, Rastogi et al. 2013).\u003c/p\u003e\r\n\r\n\u003cp\u003eOne major piece of conflicting evidence comes from a direct test of the essentiality of inflammation to IR-induced carcinogenesis. In a mouse model of lymphoma, a mutation preventing the PIDD/NEMO dependent activation of NF-kB blocks early IR-induced activation of NF-kB (4-24 h) and production of TNF-a (5-48 h) but not lymphoma, suggesting that activation of these inflammatory factors is not essential in this time period (Bock, Krumschnabel et al. 2013). However, this study examined only day one post-IR time points for NF-kB activity, and did not block production of IL6. Later activation of NF-kB or activation of other inflammation-related factors including IL6 and TGF-\u0026beta; could therefore potentially have contributed to lymphoma.\u003c/p\u003e\r\n\r\n\u003ch2\u003eKE: Increase in RONS\u003c/h2\u003e\r\n\r\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eEssentiality is High.\u003c/em\u003e\u003c/strong\u003e\u003cem\u003e The most significant support comes from the relatively large number of studies using antioxidants or other interventions to reduce RONS, which show a reduction in DNA damage and mutations. Additional support comes from experiments increasing external oxidants like H2O2, which show that RONS are independently capable of causing DNA damage and mutations. Uncertainties arise from the smaller effects of RONS on DNA damage compared with ionizing radiation. Mammary gland relevance is less certain due to the relatively few experiments in breast tissue.\u003c/em\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003eMultiple studies support the hypothesis that elevated RONS is a key part of the adverse outcome pathway for breast cancer from ionizing radiation. The strongest evidence comes from studies showing that reducing RONS also reduces DNA damage in irradiated cells and bystander cells, including genomic instability observed at later time points after IR. Free radical and NADPH oxidase inhibitors reduce the effect of IR on DNA nucleotide damage, double strand breaks, chromosomal damage, and mutations in isolated DNA and cultured cells (Winyard, Faux et al. 1992; Douki, Ravanat et al. 2006; Choi, Kang et al. 2007; Jones, Riggs et al. 2007; Ameziane-El-Hassani, Boufraqech et al. 2010; Ameziane-El-Hassani, Talbot et al. 2015; Manna, Das et al. 2015) and on nucleotide damage and double strand breaks in vivo (Pazhanisamy, Li et al. 2011; Ozyurt, Cevik et al. 2014). RONS reduction after ionizing radiation also reduces genomic instability in animals and in cloned cell lines (Dayal, Martin et al. 2008; Dayal, Martin et al. 2009; Pazhanisamy, Li et al. 2011; Bensimon, Biard et al. 2016). RONS are similarly implicated in IR effects in bystander cells. Antioxidants (including a nitric oxide scavenger) and oxidase inhibitors added before or after radiation reduce micronuclei and gamma-H2AX formation in bystander cells (Azzam, De Toledo et al. 2002; Yang, Asaad et al. 2005; Yang, Anzenberg et al. 2007). Antioxidant activity also reduces the inflammatory response to IR in animals and cultured skin cells (Berruyer, Martin et al. 2004; Das, Manna et al. 2014; Ozyurt, Cevik et al. 2014; Haddadi, Rezaeyan et al. 2017; Zhang, Zhu et al. 2017).\u003c/p\u003e\r\n\r\n\u003cp\u003eRONS are sufficient to trigger subsequent key events in this AOP. Extracellularly applied or intracellularly generated ROS (which also facilitates the formation of RNS) are capable of creating DNA damage in vitro including base damage, single and double strand breaks, and chromosomal damage (Oya, Yamamoto et al. 1986; Dahm-Daphi, Sass et al. 2000; Nakamura, Purvis et al. 2003; Gradzka and Iwanenko 2005; Ismail, Nystrom et al. 2005; Driessens, Versteyhe et al. 2009; Berdelle, Nikolova et al. 2011; Lorat, Brunner et al. 2015; Stanicka, Russell et al. 2015) and mutations (Sandhu and Birnboim 1997; Ameziane-El-Hassani, Boufraqech et al. 2010; Seager, Shah et al. 2012; Sharma, Collins et al. 2016). Similarly, decreased antioxidant activity and higher RONS is observed in cells with genomic instability (Dayal, Martin et al. 2008; Buonanno, de Toledo et al. 2011). To our knowledge, no experiments have tested whether elevating intracellular RONS alone in one group of cells can cause bystander effects in another.\u003c/p\u003e\r\n\r\n\u003ch3\u003e\u003ca name=\"_Toc2345646\"\u003eEvidence in Mammary Gland\u003c/a\u003e\u003c/h3\u003e\r\n\r\n\u003cp\u003eThe increase of RONS following IR has been shown in a wide range of cells, in vivo and in vitro, including epithelial cells, and in two studies in mammary epithelial cells (Jones, Riggs et al. 2007; Bensimon, Biard et al. 2016). Both mammary cell studies also show increased RONS and DNA damage over a day after IR in vitro and link DNA damage with elevated RONS.\u003c/p\u003e\r\n\r\n\u003ch3\u003e\u003ca name=\"_Toc2345647\"\u003eUncertainties or Inconsistencies\u003c/a\u003e\u003c/h3\u003e\r\n\r\n\u003cp\u003eThe mitigating effects of antioxidants on IR-generated DNA damage support the essentiality of RONS in producing DNA damage and mutations. However, externally applied RONS is less effective than IR at generating double strand breaks and mutations (Sandhu and Birnboim 1997; Dahm-Daphi, Sass et al. 2000; Gradzka and Iwanenko 2005; Ismail, Nystrom et al. 2005). One possible explanation for this discrepancy is that IR may elicit a higher concentration of localized RONS than can be achieved with external application of H2O2. IR deposits energy and oxidizes molecules within a relatively small area over a rapid timescale potentially permitting a very high local concentration which could precede or overwhelm local buffering capacity. In contrast, extracellularly applied H2O2 would interact with many antioxidants and other molecules on its way to the nucleus, where the concentration would slowly reach a lower steady state.\u003c/p\u003e\r\n\r\n\u003cp\u003eAs expected for RONS as a key event for DNA damage from IR, DNA damage from IR and H2O2 are additive in cells (Dahm-Daphi, Sass et al. 2000; Driessens, Versteyhe et al. 2009). Unexpectedly however, inhibiting glutathione (which should increase or sustain the effects of RONS), increases DNA damage from H2O2 but not IR. This lack of effect of glutathione inhibition on IR conflicts with multiple studies showing decreased DNA damage from IR with anti-oxidants. One possible explanation is that the concentration or reaction rate of glutathione is already inadequate to buffer the elevated RONS from IR, so further inhibition has no measurable effect.\u003c/p\u003e\r\n","quantitative_considerations":"","optional_considerations":"\u003cp\u003eBecause of the long latency of mammary tumors, the two-year rodent carcinogenicity bioassay is the primary assay for the adverse outcome of breast cancer. The assay is included in the OECD Test No. 451 and 453 for carcinogenicity and combined toxicity and carcinogenicity. \u0026nbsp;Mammary tumors are also reported in short term, sub-chronic, and chronic toxicity tests, but these tests are less sensitive due to their shorter duration.\u003c/p\u003e\r\n\r\n\u003cp\u003eThis AOP is relevant to guideline tests addressing DNA damage and mutation. MIE2: Increase in DNA damage is relevant to OECD Test Nos. 473, 475, 483, 487, and 489, which detect DNA damage in the form of single and double strand breaks, chromosomal damage and micronuclei, as well as some forms of nucleotide damage. KE1: Increase in mutation is relevant to OECD Test Nos. 471, 476, 488, and 490 for in vitro and in vivo mutations. To our knowledge no guideline tests address increases in RONS, proliferation, or inflammation, although some in vitro tests in ToxCast or in development elsewhere may reflect changes in these key events.\u003c/p\u003e\r\n","references":"\u003cp\u003e\u003ca name=\"_ENREF_1\"\u003eAmeziane-El-Hassani, R., M. Boufraqech, et al. (2010). \u0026quot;Role of H2O2 in RET/PTC1 chromosomal rearrangement produced by ionizing radiation in human thyroid cells.\u0026quot; Cancer Res 70(10): 4123-4132.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_2\"\u003eAmeziane-El-Hassani, R., M. Talbot, et al. (2015). \u0026quot;NADPH oxidase DUOX1 promotes long-term persistence of oxidative stress after an exposure to irradiation.\u0026quot; Proceedings of the National Academy of Sciences of the United States of America 112(16): 5051-5056.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_3\"\u003eAndarawewa, K. L., S. V. Costes, et al. 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(2015). \u0026quot;Induction of Non-Targeted Stress Responses in Mammary Tissues by Heavy Ions.\u0026quot; PLoS One 10(8): e0136307.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_165\"\u003eWang, Y., J. Waters, et al. (2014). \u0026quot;Clonal evolution in breast cancer revealed by single nucleus genome sequencing.\u0026quot; Nature 512(7513): 155-160.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_166\"\u003eWelsch, C. W., M. Goodrich-Smith, et al. (1981). \u0026quot;Effect of an estrogen antagonist (tamoxifen) on the initiation and progression of gamma-irradiation-induced mammary tumors in female Sprague-Dawley rats.\u0026quot; European journal of cancer \u0026amp; clinical oncology 17(12): 1255-1258.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_167\"\u003eWinyard, P. G., S. P. Faux, et al. (1992). \u0026quot;Bleomycin-induced unscheduled DNA synthesis in non-permeabilized human and rat hepatocytes is not paralleled by 8-oxo-7,8-dihydrodeoxyguanosine formation.\u0026quot; Biochem Pharmacol 44(7): 1255-1260.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_168\"\u003eYang, H., V. Anzenberg, et al. (2007). \u0026quot;The time dependence of bystander responses induced by iron-ion radiation in normal human skin fibroblasts.\u0026quot; Radiation research 168(3): 292-298.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_169\"\u003eYang, H., N. Asaad, et al. (2005). \u0026quot;Medium-mediated intercellular communication is involved in bystander responses of X-ray-irradiated normal human fibroblasts.\u0026quot; Oncogene 24(12): 2096-2103.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_170\"\u003eYang, T.-H., L. M. Craise, et al. (1992). \u0026quot;Chromosomal changes in cultured human epithelial cells transformed by low- and high-LET radiation.\u0026quot; Adv Space Res 12(2-3): 127-136.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_171\"\u003eYang, T. C., K. A. Georgy, et al. (1997). \u0026quot;Initiation of oncogenic transformation in human mammary epithelial cells by charged particles.\u0026quot; Radiat Oncol Investig 5(3): 134-138.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_172\"\u003eYang, X. R., J. K. Killian, et al. (2015). \u0026quot;Characterization of genomic alterations in radiation-associated breast cancer among childhood cancer survivors, using comparative genomic hybridization (CGH) arrays.\u0026quot; PLoS One 10(3): e0116078.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_173\"\u003eYates, L. R., M. Gerstung, et al. (2015). \u0026quot;Subclonal diversification of primary breast cancer revealed by multiregion sequencing.\u0026quot; Nat Med 21(7): 751-759.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_174\"\u003eYu, Y., R. Okayasu, et al. (2001). \u0026quot;Elevated breast cancer risk in irradiated BALB/c mice associates with unique functional polymorphism of the Prkdc (DNA-dependent protein kinase catalytic subunit) gene.\u0026quot; Cancer Res 61(5): 1820-1824.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_175\"\u003eZhang, P., A. Lo, et al. (2015). \u0026quot;Identification of genetic loci that control mammary tumor susceptibility through the host microenvironment.\u0026quot; Sci Rep 5: 8919.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_176\"\u003eZhang, Q., L. Zhu, et al. (2017). \u0026quot;Ionizing radiation promotes CCL27 secretion from keratinocytes through the cross talk between TNF-alpha and ROS.\u0026quot; J Biochem Mol Toxicol 31(3).\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_177\"\u003eZhou, H., V. N. Ivanov, et al. (2005). \u0026quot;Mechanism of radiation-induced bystander effect: role of the cyclooxygenase-2 signaling pathway.\u0026quot; Proceedings of the National Academy of Sciences of the United States of America 102(41): 14641-14646.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_178\"\u003eZhou, H., V. N. Ivanov, et al. (2008). \u0026quot;Mitochondrial function and nuclear factor-kappaB-mediated signaling in radiation-induced bystander effects.\u0026quot; Cancer Res 68(7): 2233-2240.\u003c/a\u003e\u003c/p\u003e\r\n","overall_assessment":"\u003cp\u003eSee Annex I for the assessment of the relative level of confidence in the overall AOP based on rank ordered weight of evidence elements.\u003c/p\u003e\r\n\r\n\u003cp\u003eSee Appendix 2 (KEs and KERs) for the evidence supporting each key event and key event relationship.\u003c/p\u003e\r\n","background":"\u003cp\u003eBreast cancer imposes a significant burden on women worldwide and is an important target for prevention. It is the most common invasive cancer in women with the highest rates found in North America and Europe (Ervik, Lam et al. 2016), and incidence is increasing globally (Forouzanfar, Foreman et al. 2011). In the US, the National Cancer Institute estimates that the total number of new breast cancers will increase from 283,000 to 441,000 between 2011 and 2030 (Rosenberg, Barker et al. 2015). Twin studies suggest that heritable factors explain at most a third of breast cancers and around 60% of all cancers are related to avoidable factors (Ronckers, Erdmann et al. 2005; Colditz and Wei 2012; Moller, Mucci et al. 2016), leaving significant room for prevention efforts focused on environmental factors to reduce new cases. Well-documented risk factors include tobacco and alcohol use as well as obesity, physical activity, and exposure to carcinogens (Colditz and Wei 2012).\u003c/p\u003e\r\n\r\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\r\n\r\n\u003cp\u003eBreast cancer incidence and risk varies with age, and hormonal and reproductive factors. Incidence increases with age, with rates among women increasing rapidly after age 30 and peaking around 75 years of age (NCI SEER 2016). Incidence is strongly influenced by the reproductive hormones estrogen and progesterone and by childbirth, which influence the proliferation and number of cells in the breast (Gertig, Stillman et al. 1999; Ronckers, Erdmann et al. 2005; Bijwaard, Brenner et al. 2010; Dall, Risbridger et al. 2017). Breast cancer risk increases with earlier puberty or later menopause (CGHFBC 2012; Bodicoat, Schoemaker et al. 2014), factors that increase cumulative estrogen and progesterone exposure and the number of proliferative menstrual cycles in the breast. Conversely, risk decreases in women with ovariectomies (Olson, Sellers et al. 2004; Press, Sullivan-Halley et al. 2011) and with menopause (CGHFBC 2012). Risk also decreases with number of pregnancies, breastfeeding, and increasing time since childbirth. This decrease in risk is thought to be related to the differentiation of stem cells in the breast during pregnancy and lactation and the decline in epithelial cell number after childbirth (Gertig, Stillman et al. 1999; Dall, Risbridger et al. 2017). Breast cancer incidence in men is less than 1% that of women, a difference attributed to low levels of estrogen and progesterone and few breast epithelial cells (Stang and Thomssen 2008).\u003c/p\u003e\r\n\r\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\r\n\r\n\u003cp style=\"margin-left:.5in\"\u003e\u003ca name=\"_ENREF_1\"\u003eBijwaard, H., A. Brenner, et al. (2010). \u0026quot;Breast cancer risk from different mammography screening practices.\u0026quot; \u003cu\u003eRadiation research\u003c/u\u003e \u003cstrong\u003e174\u003c/strong\u003e(3): 367-376.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp style=\"margin-left:.5in\"\u003e\u003ca name=\"_ENREF_2\"\u003eBodicoat, D. H., M. J. Schoemaker, et al. (2014). \u0026quot;Timing of pubertal stages and breast cancer risk: the Breakthrough Generations Study.\u0026quot; \u003cu\u003eBreast cancer research : BCR\u003c/u\u003e \u003cstrong\u003e16\u003c/strong\u003e(1): R18.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp style=\"margin-left:.5in\"\u003e\u003ca name=\"_ENREF_3\"\u003eCGHFBC (Collaborative Group on Hormonal Factors in Breast Cancer) (2012). \u0026quot;Menarche, menopause, and breast cancer risk: individual participant meta-analysis, including 118 964 women with breast cancer from 117 epidemiological studies.\u0026quot; \u003cu\u003eThe Lancet. Oncology\u003c/u\u003e \u003cstrong\u003e13\u003c/strong\u003e(11): 1141-1151.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp style=\"margin-left:.5in\"\u003e\u003ca name=\"_ENREF_4\"\u003eColditz, G. A. and E. K. Wei (2012). \u0026quot;Preventability of cancer: the relative contributions of biologic and social and physical environmental determinants of cancer mortality.\u0026quot; \u003cu\u003eAnnu Rev Public Health\u003c/u\u003e \u003cstrong\u003e33\u003c/strong\u003e: 137-156.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp style=\"margin-left:.5in\"\u003e\u003ca name=\"_ENREF_5\"\u003eDall, G., G. Risbridger, et al. (2017). \u0026quot;Mammary stem cells and parity-induced breast cancer protection- new insights.\u0026quot; \u003cu\u003eThe Journal of steroid biochemistry and molecular biology\u003c/u\u003e \u003cstrong\u003e170\u003c/strong\u003e: 54-60.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp style=\"margin-left:.5in\"\u003e\u003ca name=\"_ENREF_6\"\u003eErvik, M., F. Lam, et al. (2016). \u0026quot;Cancer Today.\u0026quot;\u0026nbsp;\u0026nbsp; Retrieved 03/23/2018, 2018, from http://gco.iarc.fr/today.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp style=\"margin-left:.5in\"\u003e\u003ca name=\"_ENREF_7\"\u003eForouzanfar, M. H., K. J. Foreman, et al. (2011). \u0026quot;Breast and cervical cancer in 187 countries between 1980 and 2010: a systematic analysis.\u0026quot; \u003cu\u003eThe Lancet\u003c/u\u003e \u003cstrong\u003e378\u003c/strong\u003e(9801): 1461-1484.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp style=\"margin-left:.5in\"\u003e\u003ca name=\"_ENREF_8\"\u003eGertig, D. M., I. E. Stillman, et al. (1999). \u0026quot;Association of age and reproductive factors with benign breast tissue composition.\u0026quot; \u003cu\u003eCancer epidemiology, biomarkers \u0026amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology\u003c/u\u003e \u003cstrong\u003e8\u003c/strong\u003e(10): 873-879.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp style=\"margin-left:.5in\"\u003e\u003ca name=\"_ENREF_9\"\u003eMoller, S., L. A. Mucci, et al. (2016). \u0026quot;The Heritability of Breast Cancer among Women in the Nordic Twin Study of Cancer.\u0026quot; \u003cu\u003eCancer epidemiology, biomarkers \u0026amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology\u003c/u\u003e \u003cstrong\u003e25\u003c/strong\u003e(1): 145-150.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp style=\"margin-left:.5in\"\u003e\u003ca name=\"_ENREF_10\"\u003eNCI SEER (National Cancer Institute Surveillance, E., and End Results Program), (2016). Cancer of the Breast (Invasive): SEER Incidence and U.S. Death Rates, Age-Adjusted and Age-Specific Rates, by Race and Sex. \u003cu\u003eSEER Cancer Statistics Review (1975-2014)\u003c/u\u003e, National Cancer Institute: Table 4-11.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp style=\"margin-left:.5in\"\u003e\u003ca name=\"_ENREF_11\"\u003eOlson, J. E., T. A. Sellers, et al. (2004). \u0026quot;Bilateral oophorectomy and breast cancer risk reduction among women with a family history.\u0026quot; \u003cu\u003eCancer detection and prevention\u003c/u\u003e \u003cstrong\u003e28\u003c/strong\u003e(5): 357-360.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp style=\"margin-left:.5in\"\u003e\u003ca name=\"_ENREF_12\"\u003ePress, D. J., J. Sullivan-Halley, et al. (2011). \u0026quot;Breast cancer risk and ovariectomy, hysterectomy, and tubal sterilization in the women\u0026#39;s contraceptive and reproductive experiences study.\u0026quot; \u003cu\u003eAmerican journal of epidemiology\u003c/u\u003e \u003cstrong\u003e173\u003c/strong\u003e(1): 38-47.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp style=\"margin-left:.5in\"\u003e\u003ca name=\"_ENREF_13\"\u003eRonckers, C. M., C. A. Erdmann, et al. (2005). \u0026quot;Radiation and breast cancer: a review of current evidence.\u0026quot; \u003cu\u003eBreast cancer research : BCR\u003c/u\u003e \u003cstrong\u003e7\u003c/strong\u003e(1): 21-32.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp style=\"margin-left:.5in\"\u003e\u003ca name=\"_ENREF_14\"\u003eRosenberg, P. S., K. A. Barker, et al. (2015). \u0026quot;Estrogen Receptor Status and the Future Burden of Invasive and In Situ Breast Cancers in the United States.\u0026quot; \u003cu\u003eJournal of the National Cancer Institute\u003c/u\u003e \u003cstrong\u003e107\u003c/strong\u003e(9).\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp style=\"margin-left:.5in\"\u003e\u003ca name=\"_ENREF_15\"\u003eStang, A. and C. Thomssen (2008). \u0026quot;Decline in breast cancer incidence in the United States: what about male breast cancer?\u0026quot; \u003cu\u003eBreast cancer research and treatment\u003c/u\u003e \u003cstrong\u003e112\u003c/strong\u003e(3): 595-596\u003c/a\u003e\u003c/p\u003e\r\n","user_defined_mie":"1194: Increase, DNA damage","user_defined_ao":"185: Increase, Mutations and 1192: Increased, Ductal Hyperplasia and 1193: N/A, Breast Cancer","oecd_project":"1.80","oecd_status_id":4,"graphical_representation_image_uid":"2019/05/10/6rcy7sey04_RONS_and_DNA_damage_AOP_figure.png","saaop_status_id":1,"legacy":false,"overall_assessment_file_uid":"2019/05/10/8boog7az4b_Annex_1_DNA_damage.pdf","changed_at":"2019-05-10T17:26:55.000-04:00","development_strategy":null,"known_modulating_factors":null,"assigned_license_id":252,"handbook_id":2,"project_129":false},{"id":294,"title":"Increased reactive oxygen and nitrogen species (RONS) leading to increased risk of breast cancer","short_name":"RONS leading to breast cancer","corresponding_author_id":814,"abstract":"\u003cp\u003eKnowledge about established breast carcinogens can support improved 21\u003csup\u003est\u003c/sup\u003e\u0026nbsp;century toxicological testing methods by identifying key mechanistic events. Ionizing radiation (IR) increases the risk of breast cancer, especially for women and for exposure at younger ages. We used the Adverse Outcome Pathway (AOP) framework to outline and evaluate the evidence linking ionizing radiation with breast cancer from molecular initiating events (MIE) to the adverse outcome (AO) through intermediate key events (KE). We identified prospective key events using recent literature on ionizing radiation and carcinogenesis, focusing on review articles. We searched PubMed for each key event and ionizing radiation, and used references cited in the resulting papers and targeted searches with related key words to identify additional papers. We manually curated publications and evaluated data quality. The AOP specifies that ionizing radiation directly and indirectly causes DNA damage and increases production of reactive oxygen and nitrogen species (RONS), and these are designated as MIEs.\u0026nbsp; RONS lead to DNA damage (MIE) which leads to mutations (KE). \u0026nbsp;Proliferation (KE) amplifies the effects of DNA damage and mutations leading to the AO of breast cancer. Separately, RONS (and DNA damage) also increase inflammation (KE). Inflammation contributes to direct and indirect effects (effects in cells not directly reached by IR) via positive feedback to RONS and DNA damage, and separately increases proliferation and the AO through pro-carcinogenic effects on cells and tissue. These MIEs and KEs overlap at multiple points with events characteristic of \u0026ldquo;background\u0026rdquo; induction of breast carcinogenesis, including hormone-responsive proliferation, oxidative activity, and DNA damage. These overlaps make the breast particularly susceptible to ionizing radiation and reinforce the importance of these MIEs and KEs as part of toxicological panels for carcinogenicity. The AOP identifies areas for additional research, including better description of the time and dose-dependence of MIEs and KEs in mammary tissues directly and indirectly exposed to IR.\u003c/p\u003e\r\n\r\n\u003cp\u003eThis AOP extends the characteristics of mammary carcinogens beyond DNA damage, highlighting the important role in breast cancer of chemicals that increase RONS, cell proliferation, and inflammation. Chemicals that increase these biological processes should be considered potential breast carcinogens, and predictive methods should be developed to identify chemicals that increase these processes. Ultimately, this AOP will improve methods that predict chemical breast carcinogens so that exposure can be reduced.\u003c/p\u003e\r\n","created_at":"2019-05-07T14:03:51.000-04:00","updated_at":"2023-04-29T16:03:02.000-04:00","status_id":5,"authors":"\u003cp\u003eJessica S. Helm\u003csup\u003e*\u003c/sup\u003e\u0026nbsp;and Ruthann A. Rudel\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003csup\u003e*\u003c/sup\u003eSilent Spring Institute, Newton, MA 02460\u003c/p\u003e\r\n","applicability_of_the_aop":"\u003cp\u003eWhile the key events described here are likely relevant to all tissues after exposure to IR, it is particularly relevant to the female mammary gland. While ionizing radiation causes many kinds of cancers including leukemia, lung, bladder, and thyroid cancers (BEIR 2006; Preston, Ron et al. 2007), breast cancers are among the cancers most increased by exposure to ionizing radiation (Preston, Ron et al. 2007).\u003c/p\u003e\r\n\r\n\u003cp\u003eThe lengthy and hormone-dependent developmental trajectory of the mammary gland is likely to be a major factor in its susceptibility to breast cancer. Numerous epidemiological and laboratory studies support the requirement for ovarian hormones in the risk of breast cancer from ionizing radiation (Grant, Cologne et al. 2018). Although at first examination breast cancer from ionizing radiation and hormones involve very different processes, in fact the hormone-dependent and ionizing radiation pathways of carcinogenesis intersect at multiple points that are part of breast development leaving the hormone-exposed breast more vulnerable to radiation. Two studies in humans and rats also suggest that IR can increase long term concentrations of circulating estrogen which would further amplify any additive effects, although additional evidence is needed (Suman, Johnson et al. 2012; Grant, Cologne et al. 2018).\u003c/p\u003e\r\n\r\n\u003cp\u003eOne major mechanism promoting breast cancer from ionizing radiation is the proliferation of breast stem cells. Stem cells are considered to be important to initiation because of their long life and capacity to pass on mutations to many progeny. Breast tissue is responsive to estrogen and progesterone, reproductive hormones that rise at puberty and stimulate cellular proliferation with each reproductive cycle and in pregnancy. These hormonal proliferative cycles increase the risk of cancer in breast tissue (Brisken, Hess et al. 2015). IR increases the long term proliferation of stem cells in pubertal but not adult mammary gland (Nguyen, Oketch-Rabah et al. 2011; Datta, Hyduke et al. 2012; Snijders, Marchetti et al. 2012; Suman, Johnson et al. 2012; Tang, Fernandez-Garcia et al. 2014). Replication of stem cells in the IR-exposed breast is therefore particularly elevated during puberty, likely contributing to the increased susceptibility to breast cancer from IR at this age.\u003c/p\u003e\r\n\r\n\u003cp\u003eAnother vulnerability of the breast to IR is a byproduct of proliferation: mutations. Replication itself increases the likelihood of mutations, which add to mutations arising from IR and increase the likelihood of oncogenic transformation (Atashgaran, Wrin et al. 2016). Furthermore, the high replication rate of mammary gland epithelial cells during puberty and pregnancy increases reliance on homologous recombination pathways (Kass, Lim et al. 2016). Disruption of these HR processes by IR-induced mutation or increased demand for repair can increase mutation rates and increase tumorigenesis (Mahdi, Huo et al. 2018). This disruption is particularly relevant for mammary stem cells which are highly replicating and dependent on HR but shift to NHEJ to respond to DNA damage from IR (Chang, Zhang et al. 2015). The consequence of mutations in stem cells is significant, since these cells can clonally expand to generate many mutated progeny. However, errors in stem cell division may not be the sole or primary factor driving cancer from radiation, since excess cancer risk for solid cancers at different sites from the atomic bomb are not clearly related to the number of stem cell divisions at that site (Tomasetti, Li et al. 2017).\u003c/p\u003e\r\n\r\n\u003cp\u003eThe elevated estrogen associated with development and the estrous cycle may also have direct effects that further complement the carcinogenic effects of IR. Estrogen directly increases oxidative stress in virgin (but not parous) mice (Yuan, Dietrich et al. 2016), interferes with DNA repair (Pedram, Razandi et al. 2009; Li, Chen et al. 2014) increases mutations (Mailander, Meza et al. 2006), and increases TGF-b (Jerry, Dunphy et al. 2010). Each of these effects would increase the impact of the same events arising from IR alone.\u003c/p\u003e\r\n\r\n\u003cp\u003eInflammation from the estrous cycle may also contribute to tumorigenesis following IR. Cytokines and macrophages play an integral role in mammary gland development and ductal elaboration, with alternating inflammatory, immune surveillance, and phagocytic activity occurring over each estrous cycle (Hodson, Chua et al. 2013; Atashgaran, Wrin et al. 2016; Brady, Chuntova et al. 2016). This inflammation could potentially increase IR-induced DNA damage and mutations and promote tumorigenic and invasive characteristics.\u003c/p\u003e\r\n\r\n\u003cp\u003eThe enhancement of IR induced tumorigenesis by the estrous cycle may be replicated or further enhanced by exogenous endocrine disrupting chemicals. Indeed, evidence suggests that BPA (and presumably other estrogenic chemicals) exposure in utero can increase the mammary gland\u0026rsquo;s response to progesterone during puberty (Brisken, Hess et al. 2015). This enhancement would presumably also increase the risk of breast cancer from ionizing radiation, since that risk increases with estrogen exposure and the number of menstrual cycles.\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003cstrong\u003eUncertainty arising from extrapolating from rodent and human in vitro studies to human biology\u003c/strong\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003eUncertainty in this pathway arises from inconsistencies in carcinogenesis between rodent and mouse species and strains and from incomplete information about the same mechanisms operating in humans. This raises questions about whether all evidence should be weighted equally.\u003c/p\u003e\r\n\r\n\u003cp\u003eAlmost half of the data included here is from in vitro experiments on human primary or cultured cells, which should have a high degree of relevance for this pathway in humans.\u0026nbsp; However, most of the human cells are not from mammary gland, and most of the mammary gland derived cells are cancer or immortalized cells that will not respond in exactly the same way as primary cells. Even this human data should therefore be interpreted with some caution.\u003c/p\u003e\r\n\r\n\u003cp\u003eMost of the remaining data in this AOP is from mice, with a relatively small number of rat studies. As a breast cancer model, mice share important characteristics with humans (Medina 2007; Imaoka, Nishimura et al. 2009). Mice and humans share similar epithelial cell types (Lim, Wu et al. 2010) and a similar developmental regime with the bulk of epithelial development occurring postnatally and accelerating during puberty, with differentiation during pregnancy (Medina 2007). Tumors in humans originate in the terminal ductal lobular unit, a structure that includes the lobule with secretory alveoli and the start of the collecting duct. The developmental terminal end bud structure is thought to be particularly vulnerable to carcinogens because of the presence of stem cells and proliferation, although it is not the only possible site of initiation. Similarly, tumors in mice originate in predominantly in alveoli as well as terminal end buds and small ducts (Medina 2007). Humans are more susceptible to carcinogens around puberty, and pregnancy is protective. Evidence on the role of development and reproduction in mammary carcinogenesis in mice is limited compared with rats but is consistent with sensitivity to radiation around puberty (Imaoka, Nishimura et al. 2009), and parity is protective for chemical carcinogens (Medina 2007). In addition, proliferation contributes to carcinogenesis in both mice and humans (Medina 2007).\u003c/p\u003e\r\n\r\n\u003cp\u003eHowever, mice differ from humans in some notable ways (Medina 2007). Mammary tumors are not common in mice, so susceptible strains or tumor-promoting viruses are used to increase spontaneous incidence and response to carcinogenic stimuli. This difference may be partially attributable to hormone responsiveness of tumors. Although tumors in mice depend on hormones for development, breast cancers in rats and humans are frequently hormone receptor positive, while mammary tumors in mice are not (Nandi, Guzman et al. 1995; Medina 2007; Imaoka, Nishimura et al. 2009).\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_1\"\u003eAtashgaran, V., J. Wrin, et al. (2016). \u0026quot;Dissecting the Biology of Menstrual Cycle-Associated Breast Cancer Risk.\u0026quot; Front Oncol 6: 267.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_2\"\u003eBrady, N. J., P. Chuntova, et al. (2016). \u0026quot;Macrophages: Regulators of the Inflammatory Microenvironment during Mammary Gland Development and Breast Cancer.\u0026quot; Mediators Inflamm 2016: 4549676.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_3\"\u003eBrisken, C., K. Hess, et al. (2015). \u0026quot;Progesterone and Overlooked Endocrine Pathways in Breast Cancer Pathogenesis.\u0026quot; Endocrinology 156(10): 3442-3450.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_4\"\u003eChang, C. H., M. Zhang, et al. (2015). \u0026quot;Mammary Stem Cells and Tumor-Initiating Cells Are More Resistant to Apoptosis and Exhibit Increased DNA Repair Activity in Response to DNA Damage.\u0026quot; Stem Cell Reports 5(3): 378-391.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_5\"\u003eCommittee to Assess Health Risks from Exposure to Low Levels of Ionizing Radiation (2006). Health risks from exposure to low levels of ionizing radiation : BEIR VII, Phase 2, National Research Council of the National Academies.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_6\"\u003eDatta, K., D. R. Hyduke, et al. (2012). \u0026quot;Exposure to ionizing radiation induced persistent gene expression changes in mouse mammary gland.\u0026quot; Radiat Oncol 7: 205.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_7\"\u003eGrant, E. J., J. B. Cologne, et al. (2018). \u0026quot;Bioavailable serum estradiol may alter radiation risk of postmenopausal breast cancer: a nested case-control study.\u0026quot; International journal of radiation biology 94(2): 97-105.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_8\"\u003eHodson, L. J., A. C. Chua, et al. (2013). \u0026quot;Macrophage phenotype in the mammary gland fluctuates over the course of the estrous cycle and is regulated by ovarian steroid hormones.\u0026quot; Biol Reprod 89(3): 65.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_9\"\u003eImaoka, T., M. Nishimura, et al. (2009). \u0026quot;Radiation-induced mammary carcinogenesis in rodent models: what\u0026#39;s different from chemical carcinogenesis?\u0026quot; J Radiat Res 50(4): 281-293.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_10\"\u003eJerry, D. J., K. A. Dunphy, et al. (2010). \u0026quot;Estrogens, regulation of p53 and breast cancer risk: a balancing act.\u0026quot; Cellular and molecular life sciences : CMLS 67(7): 1017-1023.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_11\"\u003eKass, E. M., P. X. Lim, et al. (2016). \u0026quot;Robust homology-directed repair within mouse mammary tissue is not specifically affected by Brca2 mutation.\u0026quot; Nat Commun 7: 13241.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_12\"\u003eLi, Z., K. Chen, et al. (2014). \u0026quot;Cyclin D1 integrates estrogen-mediated DNA damage repair signaling.\u0026quot; Cancer Res 74(14): 3959-3970.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_13\"\u003eLim, E., D. Wu, et al. (2010). \u0026quot;Transcriptome analyses of mouse and human mammary cell subpopulations reveal multiple conserved genes and pathways.\u0026quot; Breast cancer research : BCR 12(2): R21.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_14\"\u003eMahdi, A. H., Y. Huo, et al. (2018). \u0026quot;Evidence of Intertissue Differences in the DNA Damage Response and the Pro-oncogenic Role of NF-kappaB in Mice with Disengaged BRCA1-PALB2 Interaction.\u0026quot; Cancer Res 78(14): 3969-3981.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_15\"\u003eMailander, P. C., J. L. Meza, et al. (2006). \u0026quot;Induction of A.T to G.C mutations by erroneous repair of depurinated DNA following estrogen treatment of the mammary gland of ACI rats.\u0026quot; The Journal of steroid biochemistry and molecular biology 101(4-5): 204-215.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_16\"\u003eMedina, D. (2007). \u0026quot;Chemical carcinogenesis of rat and mouse mammary glands.\u0026quot; Breast Dis 28: 63-68.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_17\"\u003eNandi, S., R. C. Guzman, et al. (1995). \u0026quot;Hormones and mammary carcinogenesis in mice, rats, and humans: a unifying hypothesis.\u0026quot; Proceedings of the National Academy of Sciences of the United States of America 92(9): 3650-3657.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_18\"\u003eNguyen, D. H., H. A. Oketch-Rabah, et al. (2011). \u0026quot;Radiation acts on the microenvironment to affect breast carcinogenesis by distinct mechanisms that decrease cancer latency and affect tumor type.\u0026quot; Cancer Cell 19(5): 640-651.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_19\"\u003ePedram, A., M. Razandi, et al. (2009). \u0026quot;Estrogen inhibits ATR signaling to cell cycle checkpoints and DNA repair.\u0026quot; Mol Biol Cell 20(14): 3374-3389.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_20\"\u003ePreston, D. L., E. Ron, et al. (2007). \u0026quot;Solid cancer incidence in atomic bomb survivors: 1958-1998.\u0026quot; Radiation research 168(1): 1-64.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_21\"\u003eSnijders, A. M., F. Marchetti, et al. (2012). \u0026quot;Genetic differences in transcript responses to low-dose ionizing radiation identify tissue functions associated with breast cancer susceptibility.\u0026quot; PLoS One 7(10): e45394.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_22\"\u003eSuman, S., M. D. Johnson, et al. (2012). \u0026quot;Exposure to ionizing radiation causes long-term increase in serum estradiol and activation of PI3K-Akt signaling pathway in mouse mammary gland.\u0026quot; International journal of radiation oncology, biology, physics 84(2): 500-507.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_23\"\u003eTang, J., I. Fernandez-Garcia, et al. (2014). \u0026quot;Irradiation of juvenile, but not adult, mammary gland increases stem cell self-renewal and estrogen receptor negative tumors.\u0026quot; Stem Cells 32(3): 649-661.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_24\"\u003eTomasetti, C., L. Li, et al. (2017). \u0026quot;Stem cell divisions, somatic mutations, cancer etiology, and cancer prevention.\u0026quot; Science 355(6331): 1330-1334.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_25\"\u003eYuan, L., A. K. Dietrich, et al. (2016). \u0026quot;17beta-Estradiol alters oxidative damage and oxidative stress response protein expression in the mouse mammary gland.\u0026quot; Mol Cell Endocrinol 426: 11-21.\u003c/a\u003e\u003c/p\u003e\r\n","key_event_essentiality":"\u003cp\u003eIR appears to be a \u0026ldquo;complete\u0026rdquo; carcinogen in the mammary gland in that the toxin acts as an initiator through the formation of oxidative stress and pro-mutagenic DNA damage and (the MIEs) and as a promoter through increasing inflammation and proliferation, similar to many chemical carcinogens (Russo and Russo 1996). We have high confidence in the evidence linking stressor (IR) with adverse outcome (breast cancer). \u0026nbsp;The weight of evidence for the first pathway from RONS and DNA damage to Mutation and Proliferation is High while the weight of evidence for the second pathway from RONS to Inflammation to Proliferation and Breast Cancer is Moderate. These evaluations are based on the supporting evidence for all KEs and the considerations in Annex 1, and based on the need for additional evidence in the essentiality of Inflammation for the genesis of breast cancer.\u003c/p\u003e\r\n\r\n\u003cp\u003eThis AOP could not address the large number of related topics that interact with the key events described here. These topics include events following IR that may interact with these key events such as immune surveillance (which may change with the inflammatory environment after IR (Schreiber, Old et al. 2011; Barcellos-Hoff 2013; Lumniczky and Safrany 2015); IR effect on survival/apoptosis and interactions of apoptosis with inflammation, mutation, compensatory proliferation, and selection process; changes to DNA repair; and the role of epigenetics in carcinogenesis from IR (Daino, Nishimura et al. 2018). This AOP also does not address other influences on these key events beyond reproductive hormones and typical breast development. Subsequent contributions to this AOP should elaborate on these points.\u003c/p\u003e\r\n\r\n\u003ctable border=\"1\" cellpadding=\"0\" cellspacing=\"0\"\u003e\r\n\t\u003ctbody\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"height:20px; width:150px\"\u003e\r\n\t\t\t\u003cp\u003e\u0026nbsp;\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"height:20px; width:125px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cstrong\u003eDefining question\u003c/strong\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"height:20px; width:119px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cstrong\u003eHigh (Strong)\u003c/strong\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"height:20px; width:118px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cstrong\u003eModerate\u003c/strong\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"height:20px; width:126px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cstrong\u003eLow (Weak)\u003c/strong\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"height:79px; width:150px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cstrong\u003e2. Support for essentiality of KEs\u003c/strong\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"height:79px; width:125px\"\u003e\r\n\t\t\t\u003cp\u003eAre downstream KEs and/or the AO prevented if an upstream KE is blocked?\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"height:79px; width:119px\"\u003e\r\n\t\t\t\u003cp\u003eDirect evidence from\u003cbr /\u003e\r\n\t\t\tspecifically designed\u003cbr /\u003e\r\n\t\t\texperimental studies\u003cbr /\u003e\r\n\t\t\tillustrating essentiality for at least one of the\u003cbr /\u003e\r\n\t\t\timportant KEs\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"height:79px; width:118px\"\u003e\r\n\t\t\t\u003cp\u003eIndirect evidence that sufficient modification of an expected modulating factor attenuates or\u003cbr /\u003e\r\n\t\t\taugments a KE\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"height:79px; width:126px\"\u003e\r\n\t\t\t\u003cp\u003eNo or contradictory\u003cbr /\u003e\r\n\t\t\texperimental evidence\u003cbr /\u003e\r\n\t\t\tof the essentiality of any\u003cbr /\u003e\r\n\t\t\tof the KEs.\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"height:79px; width:150px\"\u003e\r\n\t\t\t\u003cp\u003eMIE: Increase in reactive oxygen and nitrogen species (RONS)\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd colspan=\"4\" style=\"height:79px; width:488px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cstrong\u003e\u003cem\u003eEssentiality is High.\u003c/em\u003e\u003c/strong\u003e\u003cem\u003e The most significant support comes from the relatively large number of studies using antioxidants or other interventions to reduce RONS, which show a reduction in DNA damage and mutations. Additional support comes from experiments increasing external oxidants like H2O2, which show that RONS are independently capable of causing DNA damage and mutations. Uncertainties arise from the smaller effects of RONS on DNA damage compared with ionizing radiation. Mammary gland relevance is less certain due to the relatively few experiments in breast tissue.\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"height:79px; width:150px\"\u003e\r\n\t\t\t\u003cp\u003eKE/AO: Increase in DNA damage\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd colspan=\"4\" style=\"height:79px; width:488px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cstrong\u003e\u003cem\u003eEssentiality is High.\u003c/em\u003e\u003c/strong\u003e\u003cem\u003e The essentiality of this MIE to cancer is generally accepted. Supporting evidence comes from application of mutagenic agents: the increase in DNA damage precedes mutations, proliferation, and tumorigenesis. Further indirect evidence comes from evidence for MIE1, in which antioxidants that reduce DNA damage also reduce mutations and chromosomal damage. Finally, mutations in DNA repair genes increase the risk of tumors.\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"height:79px; width:150px\"\u003e\r\n\t\t\t\u003cp\u003eKE/AO: Increase in mutation\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd colspan=\"4\" style=\"height:79px; width:488px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cstrong\u003e\u003cem\u003eEssentiality is High.\u003c/em\u003e\u003c/strong\u003e\u003cem\u003e The contribution of this MIE to cancer is generally accepted. Evidence comes from knock-out and knock-in experiments, which find that mutations in certain key genes increase tumorigenesis. However, an ongoing debate pits the singular importance of mutations against a significant role for the tissue microenvironment. This debate is fueled by transplant studies that show the importance of tissue environment for tumorigenesis and suggesting that mutations may not be sufficient for tumorigenesis.\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"height:79px; width:150px\"\u003e\r\n\t\t\t\u003cp\u003eKE: Increase, Cell Proliferation (epithelial cells)\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd colspan=\"4\" style=\"height:79px; width:488px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cstrong\u003e\u003cem\u003eEssentiality is High. \u003c/em\u003e\u003c/strong\u003e\u003cem\u003eCellular proliferation is a key characteristic of cancer cells and can lead to hyperplasia, an intermediate phase in the development of tumorigenesis.\u003c/em\u003e\u003cem\u003e Proliferation also increases the number of cells with mutations, which can further promote proliferation and/or changes to the local microenvironment.\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"height:79px; width:150px\"\u003e\r\n\t\t\t\u003cp\u003eKE/AO: Increase, Ductal Hyperplasia\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd colspan=\"4\" style=\"height:79px; width:488px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cstrong\u003e\u003cem\u003eEssentiality is High.\u003c/em\u003e\u003c/strong\u003e\u003cem\u003e Evidence comes from transplant experiments showing that non-proliferating tissue is less tumorigenic than proliferating lesions, and from interventions that reduce both proliferation and tumors. Further evidence comes from animals that are resistant to both mammary gland proliferation and tumors from ionizing radiation. Uncertainty arises from conflicting evidence on the tumorigenicity of hyperplasia, the absence of hyperplasia observed before some tumors, and spontaneous regression of tumors.\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"height:79px; width:150px\"\u003e\r\n\t\t\t\u003cp\u003eKEs: Tissue Resident Cell Activation, Increased Pro-inflammatory mediators, Leukocyte recruitment/activation\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd colspan=\"4\" style=\"height:79px; width:488px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cstrong\u003e\u003cem\u003eEssentiality is Moderate. \u003c/em\u003e\u003c/strong\u003e\u003cem\u003eThese key events were reviewed as a group. Evidence comes from using genetic modifications, antibodies, and antioxidants to reduce inflammatory and anti-inflammatory factors. These interventions reduce DNA damage, mutations, and mechanisms contributing to tumorigenesis and invasion. Uncertainty arises from conflicting effects in different genetic backgrounds and in different organs.\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\u003c/tbody\u003e\r\n\u003c/table\u003e\r\n\r\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\r\n\r\n\u003ch2\u003eMIE1: Increase in RONS\u003c/h2\u003e\r\n\r\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eEssentiality is High.\u003c/em\u003e\u003c/strong\u003e\u003cem\u003e The most significant support comes from the relatively large number of studies using antioxidants or other interventions to reduce RONS, which show a reduction in DNA damage and mutations. Additional support comes from experiments increasing external oxidants like H2O2, which show that RONS are independently capable of causing DNA damage and mutations. Uncertainties arise from the smaller effects of RONS on DNA damage compared with ionizing radiation. Mammary gland relevance is less certain due to the relatively few experiments in breast tissue.\u003c/em\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003eMultiple studies support the hypothesis that elevated RONS is a key part of the adverse outcome pathway for breast cancer from ionizing radiation. The strongest evidence comes from studies showing that reducing RONS also reduces DNA damage in irradiated cells and bystander cells, including genomic instability observed at later time points after IR. Free radical and NADPH oxidase inhibitors reduce the effect of IR on DNA nucleotide damage, double strand breaks, chromosomal damage, and mutations in isolated DNA and cultured cells (Winyard, Faux et al. 1992; Douki, Ravanat et al. 2006; Choi, Kang et al. 2007; Jones, Riggs et al. 2007; Ameziane-El-Hassani, Boufraqech et al. 2010; Ameziane-El-Hassani, Talbot et al. 2015; Manna, Das et al. 2015) and on nucleotide damage and double strand breaks in vivo (Pazhanisamy, Li et al. 2011; Ozyurt, Cevik et al. 2014). RONS reduction after ionizing radiation also reduces genomic instability in animals and in cloned cell lines (Dayal, Martin et al. 2008; Dayal, Martin et al. 2009; Pazhanisamy, Li et al. 2011; Bensimon, Biard et al. 2016). RONS are similarly implicated in IR effects in bystander cells. Antioxidants (including a nitric oxide scavenger) and oxidase inhibitors added before or after radiation reduce micronuclei and gamma-H2AX formation in bystander cells (Azzam, De Toledo et al. 2002; Yang, Asaad et al. 2005; Yang, Anzenberg et al. 2007). Antioxidant activity also reduces the inflammatory response to IR in animals and cultured skin cells (Berruyer, Martin et al. 2004; Das, Manna et al. 2014; Ozyurt, Cevik et al. 2014; Haddadi, Rezaeyan et al. 2017; Zhang, Zhu et al. 2017).\u003c/p\u003e\r\n\r\n\u003cp\u003eRONS are sufficient to trigger subsequent key events in this AOP. Extracellularly applied or intracellularly generated ROS (which also facilitates the formation of RNS) are capable of creating DNA damage in vitro including base damage, single and double strand breaks, and chromosomal damage (Oya, Yamamoto et al. 1986; Dahm-Daphi, Sass et al. 2000; Nakamura, Purvis et al. 2003; Gradzka and Iwanenko 2005; Ismail, Nystrom et al. 2005; Driessens, Versteyhe et al. 2009; Berdelle, Nikolova et al. 2011; Lorat, Brunner et al. 2015; Stanicka, Russell et al. 2015) and mutations (Sandhu and Birnboim 1997; Ameziane-El-Hassani, Boufraqech et al. 2010; Seager, Shah et al. 2012; Sharma, Collins et al. 2016). Similarly, decreased antioxidant activity and higher RONS is observed in cells with genomic instability (Dayal, Martin et al. 2008; Buonanno, de Toledo et al. 2011). To our knowledge, no experiments have tested whether elevating intracellular RONS alone in one group of cells can cause bystander effects in another.\u003c/p\u003e\r\n\r\n\u003ch3\u003e\u003ca name=\"_Toc2345646\"\u003eEvidence in Mammary Gland\u003c/a\u003e\u003c/h3\u003e\r\n\r\n\u003cp\u003eThe increase of RONS following IR has been shown in a wide range of cells, in vivo and in vitro, including epithelial cells, and in two studies in mammary epithelial cells (Jones, Riggs et al. 2007; Bensimon, Biard et al. 2016). Both mammary cell studies also show increased RONS and DNA damage over a day after IR in vitro and link DNA damage with elevated RONS.\u003c/p\u003e\r\n\r\n\u003ch3\u003e\u003ca name=\"_Toc2345647\"\u003eUncertainties or Inconsistencies\u003c/a\u003e\u003c/h3\u003e\r\n\r\n\u003cp\u003eThe mitigating effects of antioxidants on IR-generated DNA damage support the essentiality of RONS in producing DNA damage and mutations. However, externally applied RONS is less effective than IR at generating double strand breaks and mutations (Sandhu and Birnboim 1997; Dahm-Daphi, Sass et al. 2000; Gradzka and Iwanenko 2005; Ismail, Nystrom et al. 2005). One possible explanation for this discrepancy is that IR may elicit a higher concentration of localized RONS than can be achieved with external application of H2O2. IR deposits energy and oxidizes molecules within a relatively small area over a rapid timescale potentially permitting a very high local concentration which could precede or overwhelm local buffering capacity. In contrast, extracellularly applied H2O2 would interact with many antioxidants and other molecules on its way to the nucleus, where the concentration would slowly reach a lower steady state.\u003c/p\u003e\r\n\r\n\u003cp\u003eAs expected for RONS as a key event for DNA damage from IR, DNA damage from IR and H2O2 are additive in cells (Dahm-Daphi, Sass et al. 2000; Driessens, Versteyhe et al. 2009). Unexpectedly however, inhibiting glutathione (which should increase or sustain the effects of RONS), increases DNA damage from H2O2 but not IR. This lack of effect of glutathione inhibition on IR conflicts with multiple studies showing decreased DNA damage from IR with anti-oxidants. One possible explanation is that the concentration or reaction rate of glutathione is already inadequate to buffer the elevated RONS from IR, so further inhibition has no measurable effect.\u003c/p\u003e\r\n\r\n\u003ch2\u003eKE/AO: Increase in DNA damage\u003c/h2\u003e\r\n\r\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eEssentiality is High.\u003c/em\u003e\u003c/strong\u003e\u003cem\u003e The essentiality of this MIE to cancer is generally accepted. Supporting evidence comes from application of mutagenic agents: the increase in DNA damage precedes mutations, proliferation, and tumorigenesis. Further indirect evidence comes from evidence for MIE1, in which antioxidants that reduce DNA damage also reduce mutations and chromosomal damage. Finally, mutations in DNA repair genes increase the risk of tumors.\u003c/em\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003eIncreases or decreases in DNA damage are associated with corresponding increases or decreases in downstream key events in the pathway to breast cancer. An external agent (ionizing radiation) that increases DNA damage (Padula, Ponzinibbio et al. 2016) also causes chromosomal damage and increased mutations (Sandhu and Birnboim 1997; Jones, Riggs et al. 2007; Denissova, Nasello et al. 2012; Fibach and Rachmilewitz 2015), transforms cells (Yang, Craise et al. 1992; Yang, Georgy et al. 1997; Unger, Wienberg et al. 2010), and causes tumors (Poirier and Beland 1994; Little 2009). Polymorphisms or mutations in DNA repair genes affect tumor formation after ionizing radiation in animals (Yu, Okayasu et al. 2001; Umesako, Fujisawa et al. 2005) and in people (Millikan, Player et al. 2005; Andrieu, Easton et al. 2006; Broeks, Braaf et al. 2007; Bernstein, Haile et al. 2010; Brooks, Teraoka et al. 2012; Pijpe, Andrieu et al. 2012; Bernstein, Thomas et al. 2013). Consistent with these findings, antioxidants that reduce DNA damage from stressors like IR also reduce chromosomal aberrations and micronuclei arising from those stressors (Azzam, De Toledo et al. 2002; Choi, Kang et al. 2007; Jones, Riggs et al. 2007).\u003c/p\u003e\r\n\r\n\u003ch3\u003e\u003ca name=\"_Toc2345655\"\u003eEvidence in mammary gland\u003c/a\u003e\u003c/h3\u003e\r\n\r\n\u003cp\u003eThe majority of research on the effects of IR on DNA damage has been performed in tissues other than mammary gland, but several studies suggest that effects in the mammary gland (and its consequences) would be consistent with other tissues. Oxidative DNA damage in mammary cells increases immediately after exposure to IR (Haegele, Wolfe et al. 1998), and double stranded breaks, micronuclei, and (later) chromosomal aberrations appear two hours to six days after IR exposure in vivo and in vitro (Soler, Pampalona et al. 2009; Snijders, Marchetti et al. 2012; Hernandez, Terradas et al. 2013). Genomic instability was reported in genetically susceptible cells after a month of higher doses of IR (4 doses of 1.8 Gy but not 0.75 Gy) (Snijders, Marchetti et al. 2012).\u003c/p\u003e\r\n\r\n\u003ch2\u003eKE/AO: Increase in mutation\u003c/h2\u003e\r\n\r\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eEssentiality is High.\u003c/em\u003e\u003c/strong\u003e\u003cem\u003e The contribution of this MIE to cancer is generally accepted. Evidence comes from knock-out and knock-in experiments, which find that mutations in certain key genes increase tumorigenesis. However, an ongoing debate pits the singular importance of mutations against a significant role for the tissue microenvironment. This debate is fueled by transplant studies that show the importance of tissue environment for tumorigenesis and suggesting that mutations may not be sufficient for tumorigenesis.\u003c/em\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003eMutations increase transformation in culture (Wang, Su et al. 2011) and \u003ca name=\"Prolif_KE1_Essentiality\"\u003eproliferation\u003c/a\u003e and tumors in mice (Radice, Ferreira-Cornwell et al. 1997; Umesako, Fujisawa et al. 2005; de Ostrovich, Lambertz et al. 2008; Podsypanina, Politi et al. 2008; Francis, Bergsied et al. 2009; Gustin, Karakas et al. 2009; Francis, Chakrabarti et al. 2011; Tao, Xiang et al. 2017). Restoring function in mutated genes regresses tumors in animals (Martins, Brown-Swigart et al. 2006; Podsypanina, Politi et al. 2008). Mutations are common in tumors (Haag, Hsu et al. 1996; Greenman, Stephens et al. 2007; Stratton, Campbell et al. 2009; CGAN (Cancer Genome Atlas Network) 2012; Vandin, Upfal et al. 2012; Garraway and Lander 2013; Vogelstein, Papadopoulos et al. 2013; Yang, Killian et al. 2015) and tumors are largely clonal, suggesting that individual mutations offer the tumor evolutionary advantages (Wang, Waters et al. 2014; Yates, Gerstung et al. 2015; Begg, Ostrovnaya et al. 2016).\u003c/p\u003e\r\n\r\n\u003ch3\u003e\u003ca name=\"_Toc2345660\"\u003eEvidence in mammary gland\u003c/a\u003e\u003c/h3\u003e\r\n\r\n\u003cp\u003eMany of the studies in support of the proliferative and tumorigenic role of mutations are in mammary gland or breast cancers. Further support for including DNA damage and mutation in the mechanistic pathway linking ionizing radiation with breast cancer comes from the observation that variants in DNA repair genes increase the risk of mammary tumors in animals after IR (Yu, Okayasu et al. 2001; Umesako, Fujisawa et al. 2005) and increase breast cancer after IR (Millikan, Player et al. 2005; Andrieu, Easton et al. 2006; Broeks, Braaf et al. 2007; Bernstein, Haile et al. 2010; Brooks, Teraoka et al. 2012; Pijpe, Andrieu et al. 2012; Bernstein, Thomas et al. 2013). BRCA is perhaps the best known DNA repair gene linked with breast cancer risk, and several studies of these studies have suggested a link between BRCA mutation status and increased susceptibility to breast cancer following ionizing radiation, particularly in women exposed at younger ages (Pijpe, Andrieu et al. 2012).\u003c/p\u003e\r\n\r\n\u003ch3\u003e\u003ca name=\"_Toc2345661\"\u003eUncertainties or Inconsistencies\u003c/a\u003e\u003c/h3\u003e\r\n\r\n\u003cp\u003eMutations alone are not sufficient or even essential for tumor growth in mammary glands. Mammary tumor incidence following ionizing radiation varies significantly by sex and depends on the presence of ovarian hormones (Cronkite, Shellabarger et al. 1960; Segaloff and Maxfield 1971; Shellabarger, Stone et al. 1976; Holtzman, Stone et al. 1979; Holtzman, Stone et al. 1981; Welsch, Goodrich-Smith et al. 1981; Clifton, Yasukawa-Barnes et al. 1985; Solleveld, van Zwieten et al. 1986; Broerse, Hennen et al. 1987; Lemon, Kumar et al. 1989; Inano, Suzuki et al. 1991; Inano, Suzuki et al. 1996; Peterson, Servinsky et al. 2005). Tumor growth from transplanted tumor cells varies with age, parity, and lactational status (Maffini, Calabro et al. 2005; McDaniel, Rumer et al. 2006), and stroma treated with carcinogens or IR supports tumors from pre-malignant epithelial cells (Barcellos-Hoff and Ravani 2000; Maffini, Soto et al. 2004; Nguyen, Oketch-Rabah et al. 2011). While the mechanisms underlying these contextual factors have not been clearly identified, the proliferative effect of hormones on the mammary gland may serve to amplify damaged and mutated cells and modify the stromal environment to increase the likelihood of cellular transformation. Inflammatory responses including the release of cytokines and the activation of inflammatory and anti-inflammatory signaling pathways likely also amplify the effects of DNA damage and mutations through many of the same mechanisms.\u003c/p\u003e\r\n\r\n\u003ch2\u003eKE: Increase in proliferation\u003c/h2\u003e\r\n\r\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eEssentiality is High. \u003c/em\u003e\u003c/strong\u003e\u003cem\u003eCellular proliferation is a key characteristic of cancer cells (Hanahan and Weinberg 2011) and can lead to hyperplasia, an intermediate phase in the development of tumorigenesis. \u003c/em\u003e\u003cem\u003eProliferation also increases the number of cells with mutations, which can further promote proliferation and/or changes to the local microenvironment.\u003c/em\u003e\u003c/p\u003e\r\n\r\n\u003ch3\u003e\u003ca name=\"_Toc2345669\"\u003eEvidence in mammary gland\u003c/a\u003e\u003c/h3\u003e\r\n\r\n\u003cp\u003eMultiple studies show that mammary gland proliferates after IR or chemical carcinogen treatment prior to the appearance of mammary tumors. Epithelial cells proliferate following IR in vitro (Mukhopadhyay, Costes et al. 2010) and in vivo (Nguyen, Oketch-Rabah et al. 2011; Snijders, Marchetti et al. 2012; Suman, Johnson et al. 2012; Tang, Fernandez-Garcia et al. 2014). Increasing proliferation leads to hyperplasia (Korkaya, Paulson et al. 2009). Proliferative nodules and \u003ca name=\"Prolif_KE2_Essentiality\"\u003ehyperplasia\u003c/a\u003e appear in mammary terminal end bud, alveolae, and ducts of rats and mice after exposure to chemical carcinogens (Beuving, Bern et al. 1967; Beuving, Faulkin et al. 1967; Russo, Saby et al. 1977; Purnell 1980) and ionizing radiation (Faulkin, Shellabarger et al. 1967; Ullrich and Preston 1991; Imaoka, Nishimura et al. 2006). Proliferating foci precede the development of tumors (Haslam and Bern 1977; Purnell 1980) and form tumors more effectively than non-proliferating tissue (Deome, Faulkin et al. 1959; Beuving 1968; Rivera, Hill et al. 1981).\u003c/p\u003e\r\n\r\n\u003cp\u003eSupporting the essentiality of these proliferative processes to tumorigenesis, ACI rats that exhibit no mammary proliferation or hyperplasia following IR are resistant to tumors following IR (Kutanzi, Koturbash et al. 2010). Interventions reducing proliferation in susceptible PyVT and BALB/c mice also reduce mammary tumors (Luo, Fan et al. 2009; Connelly, Barham et al. 2011; Tang, Fernandez-Garcia et al. 2014).\u003c/p\u003e\r\n\r\n\u003ch3\u003e\u003ca name=\"_Toc2345670\"\u003eUncertainties or Inconsistencies\u003c/a\u003e\u003c/h3\u003e\r\n\r\n\u003cp\u003eSome studies report carcinogenesis in the absence of hyperplasia (Sinha and Dao 1974) and others do not find increased tumorigenesis from transplanted hyperplasia (Beuving, Bern et al. 1967; Haslam and Bern 1977; Sinha and Dao 1977). The failure of some proliferative foci to form tumors and the regression of some tumors when formed (Haslam and Bern 1977; Purnell 1980; Korkola and Archer 1999) suggests that proliferation may not be sufficient for sustained tumorigenesis in mammary gland.\u003c/p\u003e\r\n\r\n\u003ch2\u003eKE/AO: Increase, ductal hyperplasia\u003c/h2\u003e\r\n\r\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eEssentiality is High.\u003c/em\u003e\u003c/strong\u003e\u003cem\u003e Evidence comes from transplant experiments showing that non-proliferating tissue is less tumorigenic than proliferating lesions, and from interventions that reduce both proliferation and tumors. Further evidence comes from animals that are resistant to both mammary gland proliferation and tumors from ionizing radiation. Uncertainty arises from conflicting evidence on the tumorigenicity of hyperplasia, the absence of hyperplasia observed before some tumors, and spontaneous regression of tumors.\u003c/em\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003eHyperplasia signals the presence of excess proliferation (a key characteristic of cancer cells (Hanahan and Weinberg 2011)) and represents an intermediate phase in the development of tumorigenesis.\u003c/p\u003e\r\n\r\n\u003ch3\u003eEvidence in mammary gland\u003c/h3\u003e\r\n\r\n\u003cp\u003eMultiple studies show that mammary gland proliferates after IR or chemical carcinogen treatment prior to the appearance of mammary tumors. Proliferative nodules and hyperplasia appear in mammary terminal end bud, alveolae, and ducts of rats and mice after exposure to chemical carcinogens (Beuving, Bern et al. 1967; Beuving, Faulkin et al. 1967; Russo, Saby et al. 1977; Purnell 1980) and ionizing radiation (Faulkin, Shellabarger et al. 1967; Ullrich and Preston 1991; Imaoka, Nishimura et al. 2006). Proliferating foci precede the development of tumors (Haslam and Bern 1977; Purnell 1980) and form tumors more effectively than non-proliferating tissue (Deome, Faulkin et al. 1959; Beuving 1968; Rivera, Hill et al. 1981). Adenocarcinomas in rats appear to preferentially form from terminal end bud hyperplasia (Haslam and Bern 1977; Russo, Saby et al. 1977; Purnell 1980), similar to the origin of many breast cancers for humans and for some mice after IR (Medina and Thompson 2000).\u003c/p\u003e\r\n\r\n\u003cp\u003eSupporting the essentiality of these proliferative processes to tumorigenesis, ACI rats that exhibit no mammary proliferation or hyperplasia following IR are resistant to tumors following IR (Kutanzi, Koturbash et al. 2010). Interventions reducing proliferation in susceptible PyVT and BALB/c mice also reduce mammary tumors (Luo, Fan et al. 2009; Connelly, Barham et al. 2011).\u003c/p\u003e\r\n\r\n\u003ch3\u003eUncertainties or Inconsistencies\u003c/h3\u003e\r\n\r\n\u003cp\u003eSome studies report carcinogenesis in the absence of hyperplasia (Sinha and Dao 1974) and others do not find increased tumorigenesis from transplanted hyperplasia (Beuving, Bern et al. 1967; Haslam and Bern 1977; Sinha and Dao 1977). The failure of some lesions to form tumors and the regression of some tumors when formed (Haslam and Bern 1977; Purnell 1980; Korkola and Archer 1999) suggests that hyperplasia alone may not be sufficient for sustained tumorigenesis in mammary gland.\u003c/p\u003e\r\n\r\n\u003ch2\u003e\u0026nbsp;\u003c/h2\u003e\r\n\r\n\u003ch2\u003eKEs: Tissue resident cell activation, Increase, Pro-inflammatory mediators, Leukocyte Recruitment/Activation\u003c/h2\u003e\r\n\r\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eEssentiality is Moderate. \u003c/em\u003e\u003c/strong\u003e\u003cem\u003eThese key events were reviewed as a group. Evidence comes from using genetic modifications, antibodies, and antioxidants to reduce inflammatory and anti-inflammatory factors. These interventions reduce DNA damage, mutations, and mechanisms contributing to tumorigenesis and invasion. Uncertainty arises from conflicting effects in different genetic backgrounds and in different organs.\u003c/em\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003eTumors and tumor cells exhibit features of inflammation, and inflammation is generally understood to promote transformation and tumor progression by supporting multiple hallmarks of cancer including oxidative activity and DNA damage, survival and proliferation, angiogenesis, and invasion and metastasis (Iliopoulos, Hirsch et al. 2009; Hanahan and Weinberg 2011; Esquivel-Velazquez, Ostoa-Saloma et al. 2015).\u003c/p\u003e\r\n\r\n\u003cp\u003eMany of these cancer promoting effects of inflammation can be seen following exposure to ionizing radiation (Bisht, Bradbury et al. 2003; Elahi, Suraweera et al. 2009; Nguyen, Oketch-Rabah et al. 2011; Bouchard, Bouvette et al. 2013; Nguyen, Fredlund et al. 2013; Illa-Bochaca, Ouyang et al. 2014). Inflammatory pathways are commonly activated in breast and mammary cancers following IR (Nguyen, Oketch-Rabah et al. 2011; Nguyen, Fredlund et al. 2013; Illa-Bochaca, Ouyang et al. 2014). Polymorphisms in inflammation genes are associated with breast cancer risk from IR in radiation technologists (Schonfeld, Bhatti et al. 2010) and with susceptibility to intestinal adenoma following IR in mice (Elahi, Suraweera et al. 2009). Cytokines TGF-\u0026beta; and IL6 transform\u0026nbsp; primary human mammospheres and pre-malignant mammary epithelial cell lines in vitro and make them tumorigenic in vivo (Sansone, Storci et al. 2007; Iliopoulos, Hirsch et al. 2009; Nguyen, Oketch-Rabah et al. 2011), and inflammation related factors COX2 and TGF-\u0026beta; are required for the full effect of IR on DNA damage and transformation in vitro and mammary tumor growth and invasion in vivo (Bisht, Bradbury et al. 2003; Nguyen, Oketch-Rabah et al. 2011).\u003c/p\u003e\r\n\r\n\u003cp\u003eOne mechanism of cancer promotion involves oxidative activity and DNA damage: inflammation in response to IR increases oxidative activity in a positive feedback loop leading to increased DNA lesions and mutations. Oxidative activity mediates the increase in inflammatory markers (TNF-a and neutrophil markers) in bladder and kidney (Ozyurt, Cevik et al. 2014), and TNF-a and neutrophils increase oxidative activity (Jackson, Gajewski et al. 1989; Stevens, Bucurenci et al. 1992; Zhang, Zhu et al. 2017). Inflammatory activity from neutrophils and TNF-a and NF-kB-dependent COX2 and NO damage DNA and increase mutations by increasing oxidative activity (Jackson, Gajewski et al. 1989; Zhou, Ivanov et al. 2005). The mutations can be reduced by blocking the inflammatory factors NF-kB, COX2, TNF-a, or nitric oxide, or with antioxidants (Jackson, Gajewski et al. 1989; Zhou, Ivanov et al. 2005; Zhou, Ivanov et al. 2008; Zhang, Zhu et al. 2017). Antibodies to TNF-a or TGF-\u0026beta; reduce DNA damage in bone marrow (Burr, Robinson et al. 2010; Rastogi, Coates et al. 2012) and CHO cells (Han, Chen et al. 2010). Inhibiting TNF-a also reduces genomic instability in directly irradiated (but not bystander) lymphocytes (Moore, Marsden et al. 2005) and in bone marrow of CBA/Ca mice susceptible to IR-induced leukemia but not resistant C57BL/6 mice (Lorimore, Mukherjee et al. 2011). Inhibiting inflammatory factors NF-kB or iNOS reduces IR-induced bystander mutations in lung fibroblasts (Zhou, Ivanov et al. 2008).\u003c/p\u003e\r\n\r\n\u003cp\u003eInflammatory pathways activated by IR are also capable of promoting tumor growth and metastasis. Exposure to IR or RONS sensitizes mammary epithelial cells to respond to TGF-\u0026beta; - which is widely activated by IR (Ehrhart, Segarini et al. 1997). IR and TGF-\u0026beta; signaling leads to an epithelial to mesenchymal (EMT)-like transition, which disrupts the expression and distribution of cell adhesion molecules and multicellular organization and promotes invasion (Park, Henshall-Powell et al. 2003; Andarawewa, Erickson et al. 2007; Andarawewa, Costes et al. 2011; Iizuka, Sasatani et al. 2017). This mechanism resembles wound healing (Koh and DiPietro 2011; Perez, Vago et al. 2014; Landen, Li et al. 2016), but also resembles malignancy - invasive breast cancer cell lines overexpress TGF-\u0026beta; and respond to TGF-\u0026beta; with increased invasion (Kim, Kim et al. 2004; Gomes, Terra et al. 2012).\u0026nbsp;\u003c/p\u003e\r\n\r\n\u003cp\u003eThe response to TGF-\u0026beta; likely involves an increase in senescence in fibroblasts. IR-induced senescence releases a suite of signaling molecules including pro-inflammatory IL6 and proteases (MMPs) (Tsai, Chuang et al. 2005; Liakou, Mavrogonatou et al. 2016; Perrott, Wiley et al. 2017). The signaling molecules released by IR-senescent fibroblasts promote the disorganized tissue structure of mammary epithelial cells and the growth, EMT, and invasion of breast cancer epithelial cells or mutant epithelial cells (Tsai, Chuang et al. 2005; Liakou, Mavrogonatou et al. 2016; Perrott, Wiley et al. 2017) and 3D mammary tumor models (Sourisseau, Harrington et al. 2011). The induction of senescence in fibroblasts by IR requires TGF-\u0026beta; (Liakou, Mavrogonatou et al. 2016), and the release of the pro-invasive signaling molecules involves an IL-1 dependent activation of NF-kB (Perrott, Wiley et al. 2017). Senescence following IR also selects for a post-senescent variant of epithelial cell that is more conducive to tumorigenesis (Mukhopadhyay, Costes et al. 2010).\u003c/p\u003e\r\n\r\n\u003cp\u003eIl6 may play an important function in the carcinogenic response to IR. IL6 is expressed in mouse mammary gland after IR (Bouchard, Bouvette et al. 2013). IL6 is produced by IR-senescent fibroblasts, but may also be expressed by epithelial cells after IR since primary human mammospheres and pre-malignant mammary epithelial cell lines respond to IL6 with increased IL6 expression (Sansone, Storci et al. 2007; Iliopoulos, Hirsch et al. 2009). IL6 promotes the mobility and tumorigenesis of normal and breast cancer epithelial cells (Sansone, Storci et al. 2007; Sasser, Sullivan et al. 2007; Studebaker, Storci et al. 2008; Iliopoulos, Hirsch et al. 2009; Iliopoulos, Jaeger et al. 2010). This activity depends on transcription factor NOTCH3, which supports the renewal of stem-like cell populations (Sansone, Storci et al. 2007), and NOTCH has been implicated in multiple other studies in the proliferative response to IR in mammary epithelia (Nguyen, Oketch-Rabah et al. 2011; Marusyk, Tabassum et al. 2014; Tang, Fernandez-Garcia et al. 2014). The NF-kB/IL6/STAT3 signaling pathway generates cancer stem cells in multiple types of breast cancer cells (Iliopoulos, Hirsch et al. 2009; Iliopoulos, Jaeger et al. 2010; Iliopoulos, Hirsch et al. 2011) and is also implicated in colon and other cancers (Iliopoulos, Jaeger et al. 2010). The inflammation related transcription factor NF-kB also contributes to mammary tumorigenesis and metastasis in PyVt mice, in which mammary tumors are induced by expression of an MMTV-driven oncogene (Connelly, Barham et al. 2011). Interestingly, breast cancer fibroblasts and fibroblasts from common sites of breast cancer metastasis (bone, lung) express IL6. IL6 is required for the growth and tumor promoting effects of these fibroblasts on ER-positive cancer cells in vitro and in vivo. ER-negative breast epithelial cells release autocrine IL6 and may therefore be less dependent on IL6 from fibroblasts, although IL6 also transforms these cells (Sasser, Sullivan et al. 2007; Studebaker, Storci et al. 2008; Iliopoulos, Hirsch et al. 2009).\u003c/p\u003e\r\n\r\n\u003cp\u003eInflammation is suspected to play a role in the indirect effects of radiation, in which cells not directly targeted by radiation exhibit effects including DNA damage and RONS (Lorimore and Wright 2003; Mukherjee, Coates et al. 2014; Sprung, Ivashkevich et al. 2015). In addition to the IR-induced release of inflammatory signals that are diffusible and can trigger systemic immune responses, inflammatory factors COX2 and TGF-\u0026beta; are produced in bystander cells that are not directly irradiated but are exposed to irradiated cells or media (Zhou, Ivanov et al. 2005; Zhou, Ivanov et al. 2008; Chai, Calaf et al. 2013; Chai, Lam et al. 2013; Wang, Wu et al. 2015).\u003c/p\u003e\r\n\r\n\u003cp\u003eInflammatory factors TGF-\u0026beta;, TNF-a, COX2, and NO are implicated in the RONS (Shao, Folkard et al. 2008; Zhou, Ivanov et al. 2008; Wang, Wu et al. 2015), DNA damage (Dickey, Baird et al. 2009; Han, Chen et al. 2010; Dickey, Baird et al. 2012; Chai, Calaf et al. 2013; Chai, Lam et al. 2013; Wang, Wu et al. 2015) and mutations (Zhou, Ivanov et al. 2005; Zhou, Ivanov et al. 2008) observed in bystander cells and in the appearance of genomic instability (Moore, Marsden et al. 2005; Natarajan, Gibbons et al. 2007; Lorimore, Chrystal et al. 2008; Lorimore, Mukherjee et al. 2011) after IR. Further evidence for inflammation in indirect effects of IR come from tumors arising from mammary epithelial cells transplanted into IR exposed cleared fat pads: inflammation-related genes and pathways are upregulated or enriched in the gene expression patters of these indirectly IR-induced tumors (Nguyen, Oketch-Rabah et al. 2011; Nguyen, Fredlund et al. 2013; Illa-Bochaca, Ouyang et al. 2014).\u003c/p\u003e\r\n\r\n\u003ch3\u003e\u003ca name=\"_Toc2345676\"\u003eEvidence in mammary gland\u003c/a\u003e\u003c/h3\u003e\r\n\r\n\u003cp\u003eMany of the studies above that link inflammatory signals with increased oxidative activity, senescence, EMT, bystander effects, genomic instability, and tumorigenesis, and metastasis use mammary tissue. Since inflammation-related signals are reported after IR in mammary gland (Barcellos-Hoff, Derynck et al. 1994; Dickey, Baird et al. 2009; Datta, Hyduke et al. 2012; Snijders, Marchetti et al. 2012; Bouchard, Bouvette et al. 2013; Wang, Wu et al. 2015) inflammation likely contributes to many of the effects of IR in this tissue.\u003c/p\u003e\r\n\r\n\u003ch3\u003e\u003ca name=\"_Toc2345677\"\u003eUncertainties or inconsistencies\u003c/a\u003e\u003c/h3\u003e\r\n\r\n\u003cp\u003eThe effects of inflammation can be both pro and anti-tumorigenic. For example, in addition to TGF-\u0026beta;\u0026rsquo;s role in EMT, in mammary epithelial cells TGF-\u0026beta; is essential to apoptosis of DNA damaged cells including damage following ionizing radiation (Ewan, Henshall-Powell et al. 2002), thus limiting genomic instability (Maxwell, Fleisch et al. 2008). Inflammatory factors TNF-a and COX2 play a similar role in bone marrow of C57BL/6 mice (Lorimore, Rastogi et al. 2013). By eliminating cells with severe DNA damage and curtailing genomic instability, apoptosis (and therefore TGF-\u0026beta; or TNF-a) limits the appearance of major (possibly carcinogenic) mutations following ionizing radiation. However, apoptosis (and thus TGF-\u0026beta; or TNF-a) can indirectly promote tumorigenesis through compensatory proliferation (Loree, Koturbash et al. 2006; Fogarty and Bergmann 2017).\u003c/p\u003e\r\n\r\n\u003cp\u003eGenetic background also influences the interaction between inflammation and tumorigenesis. Polymorphisms in inflammatory genes influence susceptibility to intestinal cancer following IR (Elahi, Suraweera et al. 2009). In the SPRET outbred mouse higher baseline TGF-\u0026beta; during development decreases tumor incidence following lower doses of IR (0.1 Gy), possibly by reducing ductal branching and susceptibility (Zhang, Lo et al. 2015). Conversely, the BALB/c mouse susceptible to mammary tumors after IR has a lower baseline TGF-\u0026beta; (and a polymorphism in a DNA damage repair-related gene). Early (4 hours) after low dose (0.075 Gy) IR BALB/c mice have suppressed immune pathways and macrophage response but increased IL6, COX2, and TGF-\u0026beta; pathway activation in mammary gland compared to the tumor-resistant C57BL/6 mouse (Snijders, Marchetti et al. 2012; Bouchard, Bouvette et al. 2013).\u0026nbsp; By 1 week after IR, the BALB/c mice show TGF-\u0026beta; -dependent inflammation in the mammary gland, and by 1 month after IR, their mammary glands show proliferation (Nguyen, Martinez-Ruiz et al. 2011; Snijders, Marchetti et al. 2012), suggesting that TGF-\u0026beta; is associated with inflammation, proliferation, and mammary tumorigenesis in these mice. Consistent with this pattern, BALB/c mice that are heterozygous for TGF-\u0026beta; are more resistant to mammary tumorigenesis following IR (Nguyen, Oketch-Rabah et al. 2011). However, the BALB/c mouse also has a polymorphism in a DNA repair gene associated with IR-induced genomic instability (Yu, Okayasu et al. 2001), making it difficult to distinguish potentially overlapping mechanisms.\u003c/p\u003e\r\n\r\n\u003cp\u003eWhile inflammatory signals are associated with bystander effects including DNA damage, genomic instability, and mutation, these effects vary between organs in vivo (Chai, Calaf et al. 2013; Chai, Lam et al. 2013), by genotype (Coates, Rundle et al. 2008; Lorimore, Chrystal et al. 2008; Lorimore, Mukherjee et al. 2011), and by cell type (Chai, Calaf et al. 2013). Further research will be required to identify all the underlying factors determining differences in bystander effects, but one variable is the appearance of a protective apoptotic response to cytokines under some conditions (Lorimore, Mukherjee et al. 2011; Lorimore, Rastogi et al. 2013).\u003c/p\u003e\r\n\r\n\u003cp\u003eOne major piece of conflicting evidence comes from a direct test of the essentiality of inflammation to IR-induced carcinogenesis. In a mouse model of lymphoma, a mutation preventing the PIDD/NEMO dependent activation of NF-kB blocks early IR-induced activation of NF-kB (4-24 h) and production of TNF-a (5-48 h) but not lymphoma, suggesting that activation of these inflammatory factors is not essential in this time period (Bock, Krumschnabel et al. 2013). However, this study examined only day one post-IR time points for NF-kB activity, and did not block production of IL6. Later activation of NF-kB or activation of other inflammation-related factors including IL6 and TGF-\u0026beta; could therefore potentially have contributed to lymphoma.\u003c/p\u003e\r\n","weight_of_evidence_summary":"\u003cp\u003e\u003cstrong\u003eSupport for biological plausibility of KERs\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\r\n\r\n\u003ctable border=\"1\" cellpadding=\"0\" cellspacing=\"0\"\u003e\r\n\t\u003ctbody\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd\u003e\r\n\t\t\t\u003cp\u003e\u0026nbsp;\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd\u003e\r\n\t\t\t\u003cp\u003e\u003cstrong\u003eDefining question\u003c/strong\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd\u003e\r\n\t\t\t\u003cp\u003e\u003cstrong\u003eHigh (Strong)\u003c/strong\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd\u003e\r\n\t\t\t\u003cp\u003e\u003cstrong\u003eModerate\u003c/strong\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd\u003e\r\n\t\t\t\u003cp\u003e\u003cstrong\u003eLow (Weak)\u003c/strong\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd\u003e\r\n\t\t\t\u003cp\u003e\u0026nbsp;\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd\u003e\r\n\t\t\t\u003cp\u003ea. Is there a mechanistic relationship between KEup and KEdown consistent with established biological knowledge?\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd\u003e\r\n\t\t\t\u003cp\u003eExtensive understanding of the KER based on extensive previous documentation and broad acceptance\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd\u003e\r\n\t\t\t\u003cp\u003eKER is plausible based on analogy to accepted\u003cbr /\u003e\r\n\t\t\tbiological relationships, but scientific understanding is incomplete\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd\u003e\r\n\t\t\t\u003cp\u003eEmpirical support for\u003cbr /\u003e\r\n\t\t\tassociation between KEs, but the structural or functional relationship between them is not understood.\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd\u003e\r\n\t\t\t\u003cp\u003eMIE1 =\u0026gt; MIE2\u0026nbsp;\u003c/p\u003e\r\n\r\n\t\t\t\u003cp\u003e\u003cem\u003eIncrease in RONS leads to increase in DNA damage\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd colspan=\"4\"\u003e\r\n\t\t\t\u003cp\u003e\u003cstrong\u003e\u003cem\u003eHigh.\u003c/em\u003e\u003c/strong\u003e\u0026nbsp;\u003cem\u003eReactive oxygen and nitrogen species from oxygen and respiratory activity are generally acknowledged to damage DNA under a range of cellular conditions.\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd\u003e\r\n\t\t\t\u003cp\u003eMIE2 =\u0026gt; KE1\u003c/p\u003e\r\n\r\n\t\t\t\u003cp\u003e\u003cem\u003eDNA damage leads to mutations\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd colspan=\"4\"\u003e\r\n\t\t\t\u003cp\u003e\u003cstrong\u003e\u003cem\u003eHigh.\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003cem\u003eDNA damage in the form of nucleotide damage, single strand and double strand breaks, and complex damage can generate mutations, particularly when a damaged cell undergoes replication.\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd\u003e\r\n\t\t\t\u003cp\u003eKE1 =\u0026gt; KE2\u0026nbsp;\u003c/p\u003e\r\n\r\n\t\t\t\u003cp\u003e\u003cem\u003eMutations can promote proliferation\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd colspan=\"4\"\u003e\r\n\t\t\t\u003cp\u003e\u003cstrong\u003e\u003cem\u003eHigh.\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003cem\u003eMultiple mechanisms limit the proliferation of cells in normal biological systems. Mutations in many of the genes controlling these mechanisms promote proliferation.\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd\u003e\r\n\t\t\t\u003cp\u003eKE2 =\u0026gt; KE1\u003c/p\u003e\r\n\r\n\t\t\t\u003cp\u003e\u003cem\u003eProliferation leads to mutation\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd colspan=\"4\"\u003e\r\n\t\t\t\u003cp\u003e\u003cstrong\u003e\u003cem\u003eHigh.\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003cem\u003eProliferation is generally acknowledged to increase mutations through incorporating or amplifying the impact of unrepaired DNA damage as mutations.\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd\u003e\r\n\t\t\t\u003cp\u003eKE2 =\u0026gt; AO\u003c/p\u003e\r\n\r\n\t\t\t\u003cp\u003e\u003cem\u003eProliferation promotes breast cancer and invasion\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd colspan=\"4\"\u003e\r\n\t\t\t\u003cp\u003e\u0026nbsp;\u003cstrong\u003e\u003cem\u003eHigh.\u003c/em\u003e\u003c/strong\u003e\u0026nbsp;\u003cem\u003eIt is generally accepted that proliferation contributes to cancer. Proliferation increases the number of cells with mutations, which can further promote proliferation and/or changes to the local microenvironment.\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd\u003e\r\n\t\t\t\u003cp\u003eMIE1 =\u0026gt; KE3\u003c/p\u003e\r\n\r\n\t\t\t\u003cp\u003e\u003cem\u003eIncrease in RONS leads to inflammation\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd colspan=\"4\"\u003e\r\n\t\t\t\u003cp\u003e\u0026nbsp;\u003cstrong\u003e\u003cem\u003eModerate.\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003cem\u003eDamage from RONS can activate some inflammatory and anti-inflammatory pathways (TLR, TGF-\u0026beta;), and RONS are an essential part of the primary signaling pathways of multiple inflammatory and anti-inflammatory pathways (TLR4, TNF\u003c/em\u003e-a\u003cem\u003e, TGF-\u0026beta;, NFkB).\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd\u003e\r\n\t\t\t\u003cp\u003eKE3 =\u0026gt; MIE1\u003c/p\u003e\r\n\r\n\t\t\t\u003cp\u003e\u003cem\u003eInflammation leads to an increase in RONS\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd colspan=\"4\"\u003e\r\n\t\t\t\u003cp\u003e\u003cstrong\u003e\u003cem\u003eHigh.\u003c/em\u003e\u003c/strong\u003e\u003cem\u003e\u0026nbsp;Inflammation is commonly understood to generate RONS via inflammatory signaling and activated immune cells.\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd\u003e\r\n\t\t\t\u003cp\u003eKE3 =\u0026gt; KE2\u003c/p\u003e\r\n\r\n\t\t\t\u003cp\u003e\u003cem\u003eInflammation leads to proliferation\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd colspan=\"4\"\u003e\r\n\t\t\t\u003cp\u003e\u003cstrong\u003e\u003cem\u003eHigh.\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003cem\u003eInflammation is generally understood to lead to proliferation during recovery from inflammation.\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd\u003e\r\n\t\t\t\u003cp\u003eKE3 =\u0026gt; AO\u0026nbsp;\u003c/p\u003e\r\n\r\n\t\t\t\u003cp\u003e\u003cem\u003eInflammation promotes breast cancer and invasion\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd colspan=\"4\"\u003e\r\n\t\t\t\u003cp\u003e\u003cstrong\u003e\u003cem\u003eModerate.\u003c/em\u003e\u003c/strong\u003e\u003cem\u003e\u0026nbsp;Tissue environment is known to be a major factor in carcinogenesis, and inflammatory processes are implicated in the development and invasiveness of breast and other cancers.\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\u003c/tbody\u003e\r\n\u003c/table\u003e\r\n\r\n\u003cp\u003e\u003cstrong\u003eEmpirical support for KERs\u003c/strong\u003e\u003c/p\u003e\r\n\r\n\u003ctable border=\"1\" cellpadding=\"0\" cellspacing=\"0\"\u003e\r\n\t\u003ctbody\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd\u003e\r\n\t\t\t\u003cp\u003e\u0026nbsp;\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd\u003e\r\n\t\t\t\u003cp\u003e\u003cstrong\u003eDefining questions\u003c/strong\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd\u003e\r\n\t\t\t\u003cp\u003e\u003cstrong\u003eHigh (Strong)\u003c/strong\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd\u003e\r\n\t\t\t\u003cp\u003e\u003cstrong\u003eModerate\u003c/strong\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd\u003e\r\n\t\t\t\u003cp\u003e\u003cstrong\u003eLow (Weak)\u003c/strong\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd\u003e\r\n\t\t\t\u003cp\u003e\u003cstrong\u003eEmpirical support for KERs\u003c/strong\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd\u003e\r\n\t\t\t\u003cp\u003eDoes empirical evidence support that a change in KEup leads to an appropriate change in KEdown? Does KEup occur at lower doses and earlier time points than KE down and is the incidence of KEup \u0026gt; than that for KEdown? Inconsistencies?\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd\u003e\r\n\t\t\t\u003cp\u003eMultiple studies\u003cbr /\u003e\r\n\t\t\tshowing dependent\u003cbr /\u003e\r\n\t\t\tchange in both events\u003cbr /\u003e\r\n\t\t\tfollowing exposure to\u003cbr /\u003e\r\n\t\t\ta wide range of specific stressors. No or few critical data gaps or conflicting data.\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd\u003e\r\n\t\t\t\u003cp\u003eDemonstrated dependent change in both events following exposure to a small number of stressors. Some inconsistencies\u003cbr /\u003e\r\n\t\t\twith expected pattern that can be explained by\u003cbr /\u003e\r\n\t\t\tvarious factors.\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd\u003e\r\n\t\t\t\u003cp\u003eLimited or no studies\u003cbr /\u003e\r\n\t\t\treporting dependent\u003cbr /\u003e\r\n\t\t\tchange in both events\u003cbr /\u003e\r\n\t\t\tfollowing exposure to a\u003cbr /\u003e\r\n\t\t\tspecific stressor; and/or\u003cbr /\u003e\r\n\t\t\tsignificant inconsistencies in empirical support across taxa and species\u003cbr /\u003e\r\n\t\t\tthat don\u0026rsquo;t align with\u003cbr /\u003e\r\n\t\t\thypothesized AOP\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd\u003e\r\n\t\t\t\u003cp\u003eMIE1 =\u0026gt; MIE2\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u003cem\u003eIncrease in RONS leads to increase in DNA damage\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd colspan=\"4\"\u003e\r\n\t\t\t\u003cp\u003e\u003cstrong\u003e\u003cem\u003eHigh.\u003c/em\u003e\u003c/strong\u003e\u003cem\u003e\u0026nbsp;Multiple studies show an increase in DNA damage with RONS treatment as well as dependent changes in both RONS and DNA damage in response to stressors. DNA damage increases with RONS dose,\u0026nbsp;\u003c/em\u003e\u003cem\u003eand temporal concordance between RONS and DNA damage events following ionizing radiation is consistent with a causative relationship, although few studies examine multiple doses and time points. A small number of studies do not find double strand breaks at physiological doses, or report an increase in one key event but not the other.\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd\u003e\r\n\t\t\t\u003cp\u003eMIE2 =\u0026gt; KE1\u003c/p\u003e\r\n\r\n\t\t\t\u003cp\u003e\u003cem\u003eDNA damage leads to mutations\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd colspan=\"4\"\u003e\r\n\t\t\t\u003cp\u003e\u003cstrong\u003e\u003cem\u003eHigh.\u003c/em\u003e\u003c/strong\u003e\u003cem\u003e\u0026nbsp;It is generally accepted that DNA damage leads to mutations. Empirical support comes in part from the observation that agents which increase DNA damage also cause mutations, that DNA damage precedes the appearance of mutations, and that interventions to reduce DNA damage also reduce mutations.\u0026nbsp;\u003c/em\u003e\u003cem\u003eNone of the identified studies measure both outcomes over the same range of time points. This constitutes a readily addressable data gap.\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd\u003e\r\n\t\t\t\u003cp\u003eKE1 =\u0026gt; KE2\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u003cem\u003eMutations can promote proliferation\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd colspan=\"4\"\u003e\r\n\t\t\t\u003cp\u003e\u003cstrong\u003e\u003cem\u003eModerate.\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003cem\u003eMutations that promote\u0026nbsp;\u003ca name=\"Prolif_AOPassessment\"\u003eproliferation\u003c/a\u003e\u0026nbsp;are frequently found in cancers, and both mutation and proliferation occur in response to tumorigenic stressors like ionizing radiation. Although not measured together after stressors, mutations appear over the same time frame or prior to the appearance of proliferation. Multiple uncertainties and conflicting evidence weaken this key event relationship. The two key events differ in their dose response- mutation but not proliferation increases with ionizing radiation dose. Furthermore, a single mutation is not necessarily sufficient to increase proliferation- proliferation typically requires multiple mutations or a change in the surrounding environment. In mammary tissue,\u0026nbsp;\u003c/em\u003e\u003cem\u003estromal state strongly influences the proliferative nature of epithelial cells \u0026ndash; even epithelial cells with mutated tumor suppressors may be unable to form tumors in the absence of stromal changes.\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd\u003e\r\n\t\t\t\u003cp\u003eKE2 =\u0026gt; KE1\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u003cem\u003eProliferation leads to mutation\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd colspan=\"4\"\u003e\r\n\t\t\t\u003cp\u003e\u003cstrong\u003e\u003cem\u003eHigh.\u003c/em\u003e\u003c/strong\u003e\u0026nbsp;\u003cem\u003eWe did not evaluate the empirical support for this KER in response to IR. However\u0026nbsp;\u003c/em\u003e\u003cem\u003eproliferation or mitosis is required for some types of DNA damage to be made permanent and heritable, and further DNA damage including mutation promoting double strand breaks can occur when cells divide before DNA repair is complete.\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd\u003e\r\n\t\t\t\u003cp\u003eKE2 =\u0026gt; AO\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u003cem\u003eProliferation promotes breast cancer and invasion\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd colspan=\"4\"\u003e\r\n\t\t\t\u003cp\u003e\u003cstrong\u003e\u003cem\u003eHigh.\u003c/em\u003e\u003c/strong\u003e\u003cem\u003e\u0026nbsp;Carcinogenic agents increase proliferation and hyperplasia as well as tumors. Proliferation and hyperplasia appear prior to or at the same time as tumors, grow into carcinomas, and form mammary tumors more effectively than non-proliferating tissue. Disruption of proliferation is associated with decreased tumor growth, and tumor resistant rats do not show proliferation.\u0026nbsp;\u003c/em\u003e\u003cem\u003eHowever, the discrepancy between the non-linear proliferative and linear mammary tumor response to carcinogen dose coupled with evidence of independent occurrences of proliferation and tumorigenesis suggests that while proliferation and hyperplasia likely promote carcinogenesis, additional factors also contribute to carcinogenesis.\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd\u003e\r\n\t\t\t\u003cp\u003eMIE1 =\u0026gt; KE3\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u003cem\u003eIncrease in RONS leads to inflammation\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd colspan=\"4\"\u003e\r\n\t\t\t\u003cp\u003e\u003cstrong\u003e\u003cem\u003eModerate.\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003cem\u003eBoth RONS and inflammation increase in response to agents that increase either RONS or inflammation. Multiple studies show dose-dependent changes in both RONS and inflammation in response to stressors including ionizing radiation and antioxidants. RONS have been measured at the same or earlier time points as inflammatory markers, but additional studies are needed to characterize the inflammatory response at the earliest time points to support causation. Uncertainties come from the positive feedback from inflammation to RONS potentially interfering with attempts to establish causality, and from the large number of inflammation related factors with differing responses to stressors and experimental variation.\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd\u003e\r\n\t\t\t\u003cp\u003eKE3 =\u0026gt; MIE1\u003c/p\u003e\r\n\r\n\t\t\t\u003cp\u003e\u003cem\u003eInflammation leads to an increase in RONS\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd colspan=\"4\"\u003e\r\n\t\t\t\u003cp\u003e\u003cstrong\u003e\u003cem\u003eHigh.\u003c/em\u003e\u003c/strong\u003e\u003cem\u003e\u0026nbsp;Signals arising from inflammation can be both pro- and anti-inflammatory, and both can have effects on RONS and downstream key events. Multiple inflammation-related factors increase RONS or oxidative damage, and ionizing radiation increases both inflammation-related signaling and RONS or oxidative damage over the same time points. Interventions to reduce inflammation also reduce RONS. The dose-dependence of the response to stressors is generally consistent between the two key events, although this is based on a small number of studies with some conflicting evidence.\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd\u003e\r\n\t\t\t\u003cp\u003eKE3 =\u0026gt; KE2\u003c/p\u003e\r\n\r\n\t\t\t\u003cp\u003e\u003cem\u003eInflammation leads to proliferation\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd colspan=\"4\"\u003e\r\n\t\t\t\u003cp\u003e\u003cstrong\u003e\u003cem\u003eHigh.\u003c/em\u003e\u003c/strong\u003e\u0026nbsp;\u003cem\u003eWe did not evaluate the empirical support for this KER in response to IR. However, inflammation is generally understood to promote proliferation and survival\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd\u003e\r\n\t\t\t\u003cp\u003eKE3 =\u0026gt; AO\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; \u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u003cem\u003eInflammation promotes breast cancer and invasion\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd colspan=\"4\"\u003e\r\n\t\t\t\u003cp\u003e\u003cstrong\u003e\u003cem\u003eModerate.\u003c/em\u003e\u003c/strong\u003e\u003cem\u003e\u0026nbsp;Interventions to increase inflammatory factors increase the carcinogenic potential of targeted and non-targeted cells. Inflammation is documented at earlier time points than tumorigenesis or invasion- within minutes or hours compared to days to months for carcinogenesis, consistent with an inflammatory mechanism of tumorigenesis and invasion. Inhibition of cytokines, inflammatory signaling pathways, and downstream effectors of inflammation activity prevent transformation, tumorigenesis, and invasion following IR or stimulation of inflammatory pathways. However, the key event and the adverse outcome differ in their dose-response to ionizing radiation: inflammation always does not increase linearly with dose, while breast cancer and invasion does. Uncertainty arises from the multifunctional nature of inflammation-related pathways which may be pro- or anti-inflammatory and pro- or anti-carcinogenic based on context. Both pro- and anti-inflammatory factors may contribute to carcinogenesis- further research will be required to identify the context of each.\u003c/em\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\u003c/tbody\u003e\r\n\u003c/table\u003e\r\n","quantitative_considerations":"","optional_considerations":"\u003cp\u003eBecause of the long latency of mammary tumors, the two-year rodent carcinogenicity bioassay is the primary assay for the adverse outcome of breast cancer. The assay is included in the OECD Test No. 451 and 453 for carcinogenicity and combined toxicity and carcinogenicity. \u0026nbsp;Mammary tumors are also reported in short term, sub-chronic, and chronic toxicity tests, but these tests are less sensitive due to their shorter duration.\u003c/p\u003e\r\n\r\n\u003cp\u003eThis AOP is relevant to guideline tests addressing DNA damage and mutation. MIE2: Increase in DNA damage is relevant to OECD Test Nos. 473, 475, 483, 487, and 489, which detect DNA damage in the form of single and double strand breaks, chromosomal damage and micronuclei, as well as some forms of nucleotide damage. KE1: Increase in mutation is relevant to OECD Test Nos. 471, 476, 488, and 490 for in vitro and in vivo mutations. To our knowledge no guideline tests address increases in RONS, proliferation, or inflammation, although some in vitro tests in ToxCast or in development elsewhere may reflect changes in these key events.\u003c/p\u003e\r\n","references":"\u003cp\u003e\u003ca name=\"_ENREF_1\"\u003eAmeziane-El-Hassani, R., M. Boufraqech, et al. (2010). \u0026quot;Role of H2O2 in RET/PTC1 chromosomal rearrangement produced by ionizing radiation in human thyroid cells.\u0026quot; Cancer Res 70(10): 4123-4132.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_2\"\u003eAmeziane-El-Hassani, R., M. Talbot, et al. 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(2015). \u0026quot;Induction of Non-Targeted Stress Responses in Mammary Tissues by Heavy Ions.\u0026quot; PLoS One 10(8): e0136307.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_165\"\u003eWang, Y., J. Waters, et al. (2014). \u0026quot;Clonal evolution in breast cancer revealed by single nucleus genome sequencing.\u0026quot; Nature 512(7513): 155-160.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_166\"\u003eWelsch, C. W., M. Goodrich-Smith, et al. (1981). \u0026quot;Effect of an estrogen antagonist (tamoxifen) on the initiation and progression of gamma-irradiation-induced mammary tumors in female Sprague-Dawley rats.\u0026quot; European journal of cancer \u0026amp; clinical oncology 17(12): 1255-1258.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_167\"\u003eWinyard, P. G., S. P. Faux, et al. (1992). \u0026quot;Bleomycin-induced unscheduled DNA synthesis in non-permeabilized human and rat hepatocytes is not paralleled by 8-oxo-7,8-dihydrodeoxyguanosine formation.\u0026quot; Biochem Pharmacol 44(7): 1255-1260.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_168\"\u003eYang, H., V. Anzenberg, et al. (2007). \u0026quot;The time dependence of bystander responses induced by iron-ion radiation in normal human skin fibroblasts.\u0026quot; Radiation research 168(3): 292-298.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_169\"\u003eYang, H., N. Asaad, et al. (2005). \u0026quot;Medium-mediated intercellular communication is involved in bystander responses of X-ray-irradiated normal human fibroblasts.\u0026quot; Oncogene 24(12): 2096-2103.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_170\"\u003eYang, T.-H., L. M. Craise, et al. (1992). \u0026quot;Chromosomal changes in cultured human epithelial cells transformed by low- and high-LET radiation.\u0026quot; Adv Space Res 12(2-3): 127-136.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_171\"\u003eYang, T. C., K. A. Georgy, et al. (1997). \u0026quot;Initiation of oncogenic transformation in human mammary epithelial cells by charged particles.\u0026quot; Radiat Oncol Investig 5(3): 134-138.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_172\"\u003eYang, X. R., J. K. Killian, et al. (2015). \u0026quot;Characterization of genomic alterations in radiation-associated breast cancer among childhood cancer survivors, using comparative genomic hybridization (CGH) arrays.\u0026quot; PLoS One 10(3): e0116078.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_173\"\u003eYates, L. R., M. Gerstung, et al. (2015). \u0026quot;Subclonal diversification of primary breast cancer revealed by multiregion sequencing.\u0026quot; Nat Med 21(7): 751-759.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_174\"\u003eYu, Y., R. Okayasu, et al. (2001). \u0026quot;Elevated breast cancer risk in irradiated BALB/c mice associates with unique functional polymorphism of the Prkdc (DNA-dependent protein kinase catalytic subunit) gene.\u0026quot; Cancer Res 61(5): 1820-1824.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_175\"\u003eZhang, P., A. Lo, et al. (2015). \u0026quot;Identification of genetic loci that control mammary tumor susceptibility through the host microenvironment.\u0026quot; Sci Rep 5: 8919.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_176\"\u003eZhang, Q., L. Zhu, et al. (2017). \u0026quot;Ionizing radiation promotes CCL27 secretion from keratinocytes through the cross talk between TNF-alpha and ROS.\u0026quot; J Biochem Mol Toxicol 31(3).\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_177\"\u003eZhou, H., V. N. Ivanov, et al. (2005). \u0026quot;Mechanism of radiation-induced bystander effect: role of the cyclooxygenase-2 signaling pathway.\u0026quot; Proceedings of the National Academy of Sciences of the United States of America 102(41): 14641-14646.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_178\"\u003eZhou, H., V. N. Ivanov, et al. (2008). \u0026quot;Mitochondrial function and nuclear factor-kappaB-mediated signaling in radiation-induced bystander effects.\u0026quot; Cancer Res 68(7): 2233-2240.\u003c/a\u003e\u003c/p\u003e\r\n","overall_assessment":"\u003cp\u003eSee Annex I for the assessment of the relative level of confidence in the overall AOP based on rank ordered weight of evidence elements.\u003c/p\u003e\r\n\r\n\u003cp\u003eSee Appendix 2 (KEs and KERs) for the evidence supporting each key event and key event relationship.\u003c/p\u003e\r\n","background":"\u003cp\u003eBreast cancer imposes a significant burden on women worldwide and is an important target for prevention. It is the most common invasive cancer in women with the highest rates found in North America and Europe (Ervik, Lam et al. 2016), and incidence is increasing globally (Forouzanfar, Foreman et al. 2011). In the US, the National Cancer Institute estimates that the total number of new breast cancers will increase from 283,000 to 441,000 between 2011 and 2030 (Rosenberg, Barker et al. 2015). Twin studies suggest that heritable factors explain at most a third of breast cancers and around 60% of all cancers are related to avoidable factors (Ronckers, Erdmann et al. 2005; Colditz and Wei 2012; Moller, Mucci et al. 2016), leaving significant room for prevention efforts focused on environmental factors to reduce new cases. Well-documented risk factors include tobacco and alcohol use as well as obesity, physical activity, and exposure to carcinogens (Colditz and Wei 2012).\u003c/p\u003e\r\n\r\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\r\n\r\n\u003cp\u003eBreast cancer incidence and risk varies with age, and hormonal and reproductive factors. Incidence increases with age, with rates among women increasing rapidly after age 30 and peaking around 75 years of age (NCI SEER 2016). Incidence is strongly influenced by the reproductive hormones estrogen and progesterone and by childbirth, which influence the proliferation and number of cells in the breast (Gertig, Stillman et al. 1999; Ronckers, Erdmann et al. 2005; Bijwaard, Brenner et al. 2010; Dall, Risbridger et al. 2017). Breast cancer risk increases with earlier puberty or later menopause (CGHFBC 2012; Bodicoat, Schoemaker et al. 2014), factors that increase cumulative estrogen and progesterone exposure and the number of proliferative menstrual cycles in the breast. Conversely, risk decreases in women with ovariectomies (Olson, Sellers et al. 2004; Press, Sullivan-Halley et al. 2011) and with menopause (CGHFBC 2012). Risk also decreases with number of pregnancies, breastfeeding, and increasing time since childbirth. This decrease in risk is thought to be related to the differentiation of stem cells in the breast during pregnancy and lactation and the decline in epithelial cell number after childbirth (Gertig, Stillman et al. 1999; Dall, Risbridger et al. 2017). Breast cancer incidence in men is less than 1% that of women, a difference attributed to low levels of estrogen and progesterone and few breast epithelial cells (Stang and Thomssen 2008).\u003c/p\u003e\r\n\r\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_1\"\u003eBijwaard, H., A. Brenner, et al. (2010). \u0026quot;Breast cancer risk from different mammography screening practices.\u0026quot;\u0026nbsp;\u003cu\u003eRadiation research\u003c/u\u003e\u003cstrong\u003e174\u003c/strong\u003e(3): 367-376.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_2\"\u003eBodicoat, D. H., M. J. Schoemaker, et al. (2014). \u0026quot;Timing of pubertal stages and breast cancer risk: the Breakthrough Generations Study.\u0026quot;\u0026nbsp;\u003cu\u003eBreast cancer research : BCR\u003c/u\u003e\u0026nbsp;\u003cstrong\u003e16\u003c/strong\u003e(1): R18.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_3\"\u003eCGHFBC (Collaborative Group on Hormonal Factors in Breast Cancer) (2012). \u0026quot;Menarche, menopause, and breast cancer risk: individual participant meta-analysis, including 118 964 women with breast cancer from 117 epidemiological studies.\u0026quot;\u0026nbsp;\u003cu\u003eThe Lancet. Oncology\u003c/u\u003e\u0026nbsp;\u003cstrong\u003e13\u003c/strong\u003e(11): 1141-1151.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_4\"\u003eColditz, G. A. and E. K. Wei (2012). \u0026quot;Preventability of cancer: the relative contributions of biologic and social and physical environmental determinants of cancer mortality.\u0026quot;\u0026nbsp;\u003cu\u003eAnnu Rev Public Health\u003c/u\u003e\u0026nbsp;\u003cstrong\u003e33\u003c/strong\u003e: 137-156.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_5\"\u003eDall, G., G. Risbridger, et al. (2017). \u0026quot;Mammary stem cells and parity-induced breast cancer protection- new insights.\u0026quot;\u0026nbsp;\u003cu\u003eThe Journal of steroid biochemistry and molecular biology\u003c/u\u003e\u0026nbsp;\u003cstrong\u003e170\u003c/strong\u003e: 54-60.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_6\"\u003eErvik, M., F. Lam, et al. (2016). \u0026quot;Cancer Today.\u0026quot;\u0026nbsp;\u0026nbsp; Retrieved 03/23/2018, 2018, from http://gco.iarc.fr/today.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_7\"\u003eForouzanfar, M. H., K. J. Foreman, et al. (2011). \u0026quot;Breast and cervical cancer in 187 countries between 1980 and 2010: a systematic analysis.\u0026quot;\u0026nbsp;\u003cu\u003eThe Lancet\u003c/u\u003e\u0026nbsp;\u003cstrong\u003e378\u003c/strong\u003e(9801): 1461-1484.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_8\"\u003eGertig, D. M., I. E. Stillman, et al. (1999). \u0026quot;Association of age and reproductive factors with benign breast tissue composition.\u0026quot;\u0026nbsp;\u003cu\u003eCancer epidemiology, biomarkers \u0026amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology\u003c/u\u003e\u0026nbsp;\u003cstrong\u003e8\u003c/strong\u003e(10): 873-879.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_9\"\u003eMoller, S., L. A. Mucci, et al. (2016). \u0026quot;The Heritability of Breast Cancer among Women in the Nordic Twin Study of Cancer.\u0026quot;\u0026nbsp;\u003cu\u003eCancer epidemiology, biomarkers \u0026amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology\u003c/u\u003e\u0026nbsp;\u003cstrong\u003e25\u003c/strong\u003e(1): 145-150.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_10\"\u003eNCI SEER (National Cancer Institute Surveillance, E., and End Results Program), (2016). Cancer of the Breast (Invasive): SEER Incidence and U.S. Death Rates, Age-Adjusted and Age-Specific Rates, by Race and Sex.\u0026nbsp;\u003cu\u003eSEER Cancer Statistics Review (1975-2014)\u003c/u\u003e, National Cancer Institute: Table 4-11.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_11\"\u003eOlson, J. E., T. A. Sellers, et al. (2004). \u0026quot;Bilateral oophorectomy and breast cancer risk reduction among women with a family history.\u0026quot;\u0026nbsp;\u003cu\u003eCancer detection and prevention\u003c/u\u003e\u0026nbsp;\u003cstrong\u003e28\u003c/strong\u003e(5): 357-360.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_12\"\u003ePress, D. J., J. Sullivan-Halley, et al. (2011). \u0026quot;Breast cancer risk and ovariectomy, hysterectomy, and tubal sterilization in the women\u0026#39;s contraceptive and reproductive experiences study.\u0026quot;\u0026nbsp;\u003cu\u003eAmerican journal of epidemiology\u003c/u\u003e\u0026nbsp;\u003cstrong\u003e173\u003c/strong\u003e(1): 38-47.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_13\"\u003eRonckers, C. M., C. A. Erdmann, et al. (2005). \u0026quot;Radiation and breast cancer: a review of current evidence.\u0026quot;\u0026nbsp;\u003cu\u003eBreast cancer research : BCR\u003c/u\u003e\u0026nbsp;\u003cstrong\u003e7\u003c/strong\u003e(1): 21-32.\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_14\"\u003eRosenberg, P. S., K. A. Barker, et al. (2015). \u0026quot;Estrogen Receptor Status and the Future Burden of Invasive and In Situ Breast Cancers in the United States.\u0026quot;\u0026nbsp;\u003cu\u003eJournal of the National Cancer Institute\u003c/u\u003e\u0026nbsp;\u003cstrong\u003e107\u003c/strong\u003e(9).\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003ca name=\"_ENREF_15\"\u003eStang, A. and C. Thomssen (2008). \u0026quot;Decline in breast cancer incidence in the United States: what about male breast cancer?\u0026quot;\u0026nbsp;\u003cu\u003eBreast cancer research and treatment\u003c/u\u003e\u0026nbsp;\u003cstrong\u003e112\u003c/strong\u003e(3): 595-596\u003c/a\u003e\u003c/p\u003e\r\n","user_defined_mie":"1632: Increase in reactive oxygen and nitrogen species (RONS)","user_defined_ao":"1194: Increase, DNA damage and 185: Increase, Mutations and 1192: Increased, Ductal Hyperplasia and 1193: N/A, Breast Cancer","oecd_project":"1.80","oecd_status_id":4,"graphical_representation_image_uid":"2019/05/10/56rx1q3kl9_RONS_and_DNA_damage_AOP_figure.png","saaop_status_id":1,"legacy":false,"overall_assessment_file_uid":"2019/05/10/1cwrlx4iom_Annex_1_RONS.pdf","changed_at":"2019-05-10T17:22:35.000-04:00","development_strategy":null,"known_modulating_factors":null,"assigned_license_id":253,"handbook_id":2,"project_129":false},{"id":439,"title":"Activation of the AhR leading to metastatic breast cancer ","short_name":"AhR activation to metastatic breast cancer","corresponding_author_id":8894,"abstract":"\u003cp\u003eBreast cancer is the deadliest cancer in women with a poor prognosis in case of metastatic breast cancer. The role of the environments in the formation of metastasis has been suggested. We hypothesized that activation of the AhR (MIE), a xenobiotic receptor, could lead to breast cancer metastasis (AO), through different KEs, constituting a new AOP.\u003c/p\u003e\r\n\r\n\u003cp\u003eAn artificial intelligence tool (AOP-helpfinder), which screens the available literature, was used to collect all existing scientific abstracts to build a novel AOP, using a list of key words. Four hundred and seven abstracts were found containing at least a word from our MIE list and either one word from our AO or KE list. A manual curation retained 113 pertinent articles, which were also screened using PubTator. \u003cspan style=\"font-size:12pt\"\u003e\u003cspan style=\"font-family:Arial,sans-serif\"\u003eFrom these analyses, an AOP was created linking the activation of the AhR to breast cancer related death through decreased apoptosis, inflammation, endothelial cell migration, and increased mortality. These KEs promote an increased tumor growth, angiogenesis and invasion which leads to breast cancer metastasis.\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003eThe evidence of the proposed AOP was weighted using the tailored Bradford Hill criteria and the \u003cspan style=\"font-size:12.0pt\"\u003e\u003cspan style=\"font-family:\u0026quot;Arial\u0026quot;,sans-serif\"\u003eAOP developers\u0026rsquo; handbook\u003c/span\u003e\u003c/span\u003e (\u003cspan style=\"font-size:12.0pt\"\u003e\u003cspan style=\"font-family:\u0026quot;Arial\u0026quot;,sans-serif\"\u003e\u003ca href=\"https://aopwiki.org/handbooks/\" style=\"color:blue; text-decoration:underline\"\u003ehttps://aopwiki.org/handbooks/\u003c/a\u003e\u003c/span\u003e\u003c/span\u003e). The confidence in our AOP\u0026nbsp;and the biological plausibility was considered strong. Indeed, \u003cem\u003ein vitro\u003c/em\u003e and i\u003cem\u003en vivo\u003c/em\u003e findings on multiple types of breast cancers (with or without oesrtogen receptors, for instanace) supported our proposed AOP. An\u0026nbsp;\u003cem\u003ein vitro\u003c/em\u003e\u0026nbsp;validation must be carried out, but our review proposes a strong relationship between AhR activation and breast cancer metastasis with an innovative use of an artificial intelligence literature search.\u003c/p\u003e\r\n\r\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\r\n\r\n\u003cp\u003eThis work was published in Envionnmental International:\u0026nbsp;\u003ca href=\"https://doi.org/10.1016/j.envint.2022.107323\" rel=\"noreferrer noopener\" target=\"_blank\" title=\"Persistent link using digital object identifier\"\u003ehttps://doi.org/10.1016/j.envint.2022.107323\u003c/a\u003e\u003c/p\u003e\r\n","created_at":"2022-02-15T15:06:25.000-05:00","updated_at":"2026-03-31T13:09:10.000-04:00","status_id":6,"authors":"\u003cp\u003eXavier Coumoul\u003c/p\u003e\r\n\r\n\u003cp\u003eRobert Barouki\u003c/p\u003e\r\n\r\n\u003cp\u003eMeriem Koual\u003c/p\u003e\r\n\r\n\u003cp\u003eKarine Audouze\u003c/p\u003e\r\n\r\n\u003cp\u003eCeline Tomkiewicz\u003c/p\u003e\r\n","applicability_of_the_aop":"\u003cdiv style=\"background:#eeeeee; border:1px solid #cccccc; padding:5px 10px\"\u003e\u003csmall\u003eThe\u0026nbsp;\u003cem\u003ebiological applicability domain\u003c/em\u003e\u0026nbsp;of the putative AOP concerned mainly females of menstrual of post-menopausal age. Indeed, existing cell lines were derived from women of menstrual of post-menopausal age and\u0026nbsp;\u003cem\u003ein vivo\u003c/em\u003e, studies were performed on mice of reproductive age. Only one study used the zebra fish larvae (\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0430\" name=\"bb0430\"\u003eNarasimhan et al., 2018 May 7\u003c/a\u003e). However, it could be extrapolated to men. Indeed, breast cancers in men present similar tumor characteristics and no work has found diverging functions of the AhR between men and women. Moreover, no difference in AhR expression has been characterized between men and women. Furthermore, our AOP concerns ER-positive and triple negative cells lines.\u003c/small\u003e\u003c/div\u003e\r\n\r\n\u003cdiv style=\"background:#eeeeee; border:1px solid #cccccc; padding:5px 10px\"\u003e\u003csmall\u003eStudies were carried out in humans, mice, and zebrafish (xenotransplant studies, no mammary gland) (i.e. PubTator results) and it can be hypothesized that this AOP is conserved across mammals. Indeed, the AhR is a very conserved and ancient protein (\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0205\" name=\"bb0205\"\u003eHahn, 2002 Sep 20\u003c/a\u003e). However, since the sensitivity to adverse events are variable among taxa, we can only postulate this AOP in human and mice (\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0305\" name=\"bb0305\"\u003eKorkalainen et al., 2001 Aug 3\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0080\" name=\"bb0080\"\u003eCohen-Barnhouse et al., 2011 Jan\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0125\" name=\"bb0125\"\u003eDoering et al., 2013 Mar\u003c/a\u003e).\u003c/small\u003e\u003c/div\u003e\r\n\r\n\u003cdiv style=\"background:#eeeeee; border:1px solid #cccccc; padding:5px 10px\"\u003e\u0026nbsp;\u003c/div\u003e\r\n\r\n\u003cdiv style=\"background:#eeeeee; border:1px solid #cccccc; padding:5px 10px\"\u003e\u003csmall\u003eThe AhR is a fascinating yet complex receptor since its activation is ligand and cell dependent. To avoid more bias, we decided to limit our AOP to breast cancer. First, this cancer is the most frequent female malignancy, which makes it a major public health concern. Second, this illness is hormonal-dependent and therefore the impact of the environment, through the AhR, can be strongly suggested. However, we have reasons to believe this AOP could be extrapolated to other cancers which share common regulatory pathways (\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0335\" name=\"bb0335\"\u003eLarigot et al., 2022\u003c/a\u003e). The AhR is overexpressed not only in breast cancer but also in lung, liver, stomach, head \u0026amp; neck, cervix, and ovarian cancer (\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0590\" name=\"bb0590\"\u003eStanford et al., 2016\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0115\" name=\"bb0115\"\u003eDiNatale et al., 2010 Aug 6\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0385\" name=\"bb0385\"\u003eLiu et al., 2013 Aug\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0595\" name=\"bb0595\"\u003eStanford et al., 2016 Aug\u003c/a\u003e). Moreover, in these cancers, the level of expression is correlated to the stage of the disease (\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0730\" name=\"bb0730\"\u003eZudaire et al., 2008\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0300\" name=\"bb0300\"\u003eKoliopanos et al., 2002 Sep 5\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0060\" name=\"bb0060\"\u003eChang et al., 2007 Jan 1\u003c/a\u003e). Additionally, Moenniks\u0026nbsp;\u003cem\u003eet al.\u003c/em\u003e\u0026nbsp;found that mice with constitutively active AhR had more liver tumors than wild type mice (55%\u0026nbsp;\u003cem\u003eversus\u003c/em\u003e\u0026nbsp;6%) (\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0415\" name=\"bb0415\"\u003eMoennikes et al., 2004 Jul 15\u003c/a\u003e).\u0026nbsp;\u003cem\u003eIn vitro\u003c/em\u003e\u0026nbsp;evidence suggests that the AhR activation could promote a more aggressive phenotype to renal, lung, head and neck, and urothelial cancer through an increase in invasion, migration, and resistance to apoptosis which constitute representative key events of our AOP (\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0730\" name=\"bb0730\"\u003eZudaire et al., 2008\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0595\" name=\"bb0595\"\u003eStanford et al., 2016 Aug\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0245\" name=\"bb0245\"\u003eIshida et al., 2015 Jul 15\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0240\" name=\"bb0240\"\u003eIshida et al., 2010 Feb\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0120\" name=\"bb0120\"\u003eDiry et al., 2006 Sep 7\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0250\" name=\"bb0250\"\u003eJohn et al., 2014 Oct\u003c/a\u003e). Besides, an AOP associating AhR activation and lung cancer initiation is currently under development (\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0010\" name=\"bb0010\"\u003eAOP, 2021\u003c/a\u003e) (\u003ca href=\"https://aopwiki.org/aops/417\" rel=\"noreferrer noopener\" target=\"_blank\"\u003e\u003cu\u003ehttps://aopwiki.org/aops/417\u003c/u\u003e\u003c/a\u003e, accessed May 2022).\u003c/small\u003e\u003c/div\u003e\r\n\r\n\u003cdiv style=\"background:#eeeeee; border:1px solid #cccccc; padding:5px 10px\"\u003e\u003csmall\u003e\u003cspan style=\"font-size:11.0pt\"\u003e\u003cspan style=\"background-color:white\"\u003e\u003cspan style=\"font-family:\u0026quot;Times New Roman\u0026quot;,serif\"\u003eThe applicability of this AOP is further constrained by the context-dependent nature of AhR signaling. In addition to ligand specificity, the biological outcome of AhR activation depends on the duration and intensity of activation, the cellular context, and interactions with other signaling pathways. AhR is involved in physiological processes including maintenance of tissue homeostasis, regulation of immune responses, and control of cell differentiation (Stockinger et al., 2014; Rothhammer and Quintana, 2019). Under these conditions, AhR activation may exert protective or anti-tumorigenic effects. In contrast, sustained or dysregulated activation, particularly in the presence of persistent environmental ligands or within a permissive tumor microenvironment, may promote pro-tumorigenic pathways associated with cancer progression. Therefore, this AOP is considered most applicable to situations in which homeostatic and compensatory mechanisms are altered or overwhelmed, and should not be interpreted as a universal consequence of AhR activation.\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/small\u003e\u003c/div\u003e\r\n\r\n\u003cdiv style=\"background:#eeeeee; border:1px solid #cccccc; padding:5px 10px\"\u003e\u003csmall\u003eLikewise, our AOP covers only breast cancer progression and not initiation. The mechanisms of breast cancer initiation are different from the metastatic pathway, but the AhR could also be involved in breast cancer initiation.\u0026nbsp;\u003cem\u003eIn vitro\u003c/em\u003e, it was noted that human mammary benign cells with a high level of AhR had an increase in cell proliferation, and migration, and potentially display EMT-like features (\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0050\" name=\"bb0050\"\u003eBrooks and Eltom, 2011 Jun\u003c/a\u003e).\u0026nbsp;\u003cem\u003eIn vivo\u003c/em\u003e, mice fed with 7,12-dimethylbenz[a]anthracene (DMBA, an AhR activator and a potent mutagen) had an increased risk of mammary tumors, with higher AhR expression (\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0090\" name=\"bb0090\"\u003eCurrier et al., 2005\u003c/a\u003e). Strangely in regard of the deadly outcomes associated with aggressive breast tumors, the number of studies focusing on this specific aspect of mammary carcinogenesis is limited and therefore, epidemiological data on the effects of the exposome in breast cancer aggressiveness is scarce. Indeed, occupational exposure is difficult to quantify, and patients are usually exposed to a mixture of pollutants and not a single pollutant in a chronic way. A memory bias cannot be excluded since the half-life of TCDD, for instance, is 7\u0026ndash;11\u0026nbsp;years (\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0490\" name=\"bb0490\"\u003ePirkle et al., 1989\u003c/a\u003e). Industrial accidents, such as the Seveso incident, studied the increase in breast cancer incidence but did not record breast cancer aggressiveness since it is more complex to quantify. At an early stage, breast cancer has a favorable prognosis whereas the therapeutic challenge lies in the treatment of breast cancer metastases. Therefore, even though epidemiologic and cell evidence suggests that exposure to pollutants and Ahr activation could promote breast cancer initiation, we chose to study breast cancer progression, the most complex situation (\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0475\" name=\"bb0475\"\u003ePesatori et al., 2009 Sep\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0670\" name=\"bb0670\"\u003eWarner et al., 2002 Jul\u003c/a\u003e).\u003c/small\u003e\u003c/div\u003e\r\n\r\n\u003cdiv style=\"background:#eeeeee; border:1px solid #cccccc; padding:5px 10px\"\u003e\u003csmall\u003e\u003cspan style=\"font-size:12pt\"\u003e\u003cspan style=\"background-color:white\"\u003e\u003cspan style=\"font-family:\u0026quot;Times New Roman\u0026quot;,serif\"\u003e\u003cspan style=\"font-size:11.0pt\"\u003eIn addition, the biological applicability domain of this AOP should be restricted not only by sex, species, and life stage, but also by tumor subtype, cellular plasticity, and tumor microenvironmental context. AhR signaling is now recognized as a ligand-, cell type-, and context-dependent pathway, and its downstream consequences cannot be assumed to be uniform across all breast cancers. In breast cancer, the most consistent mechanistic evidence available for this AOP concerns ER-positive and triple-negative models, whereas HER2-positive disease remains underrepresented and should therefore be considered outside the strongest evidence base at this stage. Moreover, several key processes relevant to metastatic competence, including epithelial\u0026ndash;mesenchymal plasticity/stem-like features, endocrine resistance, inflammatory signaling, angiogenesis, and therapy resistance, are modulated by cross-talk between AhR and ER signaling, as well as by interactions with hypoxia- and metabolism-related pathways; these interactions are not obligatory in every AhR-activated setting and likely contribute to the heterogeneous and sometimes indirect causal evidence linking AhR activation to the adverse outcome. Beyond tumor-intrinsic effects, AhR also shapes the tumor microenvironment, including immune-cell polarization, regulatory T-cell programs, dendritic-cell function, stromal remodeling, and metabolite-driven signaling such as the kynurenine pathway, all of which may either facilitate or constrain tumor progression depending on ligand class and local context. Consequently, AOP 439 should be interpreted as most applicable to established breast cancers in which sustained or dysregulated AhR activation occurs within a permissive pro-metastatic microenvironment, rather than as a universal consequence of AhR activation across all breast cancer subtypes or exposure scenarios (Murray et al., 2014; Rothhammer and Quintana, 2019; Sweeney et al., 2022; Safe and Zhang, 2022; Griffith and Frankel, 2024).\u003cbr /\u003e\r\n\u003cbr /\u003e\r\nA further limitation of the applicability domain of this AOP is that AhR activation cannot be interpreted as a universally pro-tumorigenic molecular initiating event in breast cancer. Rather, the available literature indicates that AhR signaling is highly context-dependent, and may exert either tumor-promoting or tumor-restraining effects depending on the ligand involved, the duration and magnitude of activation, tumor subtype, cell differentiation state, and microenvironmental context (Safe et al., 2013; Murray et al., 2014; Larigot et al., 2022). In the setting most relevant to AOP 439, the evidence is strongest for a pro-metastatic role in established breast cancer models, particularly through pathways related to migration, invasion, resistance to apoptosis, inflammatory signaling, angiogenesis, and immune modulation (Opitz et al., 2011; Novikov et al., 2016; Goode et al., 2014). For instance, activation of the TDO2\u0026ndash;kynurenine\u0026ndash;AhR axis has been shown to promote anoikis resistance and metastatic potential in triple-negative breast cancer models (D\u0026rsquo;Amato et al., 2015; Opitz et al., 2011). However, this pro-tumorigenic profile does not apply uniformly across all biological contexts. Several studies report that AhR activation may also contribute to differentiation, cell cycle regulation, or tumor suppression under specific conditions, including in non-transformed mammary cells or depending on ligand specificity (Brooks and Eltom, 2011; Safe and Zhang, 2022). Moreover, cross-talk between AhR and estrogen receptor signaling, as well as interactions with hypoxia-inducible and metabolic pathways, can significantly alter downstream effects and contribute to heterogeneous outcomes (Safe et al., 2013; Swedenborg et al., 2009). The tumor microenvironment also plays a critical modulatory role, as AhR signaling influences immune cell function, including regulatory T cells and dendritic cells, as well as stromal interactions and metabolite-driven signaling such as the kynurenine pathway (Rothhammer and Quintana, 2019; Stockinger et al., 2014). Importantly, the current evidence base supporting this AOP is largely derived from ER-positive and triple-negative breast cancer models, whereas HER2-positive disease remains underrepresented, limiting generalizability across all subtypes (Goode et al., 2014; Larigot et al., 2022). Accordingly, this AOP should be interpreted as applying primarily to breast cancer progression toward metastatic competence under conditions of sustained or dysregulated AhR activation in a permissive pro-tumor microenvironment, and not as a universal consequence of AhR activation across all breast cancer contexts. Finally, the presence of conflicting evidence in the literature reflects the intrinsic complexity of AhR biology and is now explicitly acknowledged as a factor that limits the generalizability of this AOP while not invalidating its relevance within the specific contexts described above.\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/small\u003e\u003c/div\u003e\r\n","key_event_essentiality":"\u003cp\u003e\u0026nbsp;\u003c/p\u003e\r\n\r\n\u003ctable border=\"1\" bordercolor=\"#ccc\" cellpadding=\"5\" cellspacing=\"0\" style=\"border-collapse:collapse\"\u003e\r\n\t\u003ctbody\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003eKEY EVENT\u003c/span\u003e\u003c/td\u003e\r\n\t\t\t\u003ctd\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003eLEVEL OF ESSENTIALITY\u003c/span\u003e\u003c/td\u003e\r\n\t\t\t\u003ctd\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003eEVIDENCE\u003c/span\u003e\u003c/td\u003e\r\n\t\t\t\u003ctd\u003e\u0026nbsp;\u003c/td\u003e\r\n\t\t\t\u003ctd\u003e\u0026nbsp;\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cstrong\u003eKE 1262\u0026nbsp; :\u0026nbsp;decreased apoptosis\u0026nbsp;\u003c/strong\u003e\u003c/span\u003e\u003c/td\u003e\r\n\t\t\t\u003ctd\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003eStrong\u003c/span\u003e\u003c/td\u003e\r\n\t\t\t\u003ctd\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003eA decrease in apoptosis is an essentiel element in promoting tumor growth (Hannahan , Fulda). Indeed, in case of a decrease in cell death, the tumor will continue to grow.\u0026nbsp;\u003cspan style=\"font-size:12.0pt\"\u003eFirst, A decrase in apoptosis causes uncontrolled Cell Proliferation. Healthy tissues maintain homeostasis through a balance between cell proliferation and apoptosis. When apoptosis is compromised, cells that should undergo programmed cell death survive and continue dividing. This leads to an unchecked increase in cell number, forming the initial tumor mass. [Hanahan \u0026amp; Weinberg, 2011]. Second, cancer cells sustain proliferative signaling. Many cancers harbor mutations that activate pro-proliferative signaling pathways like Ras or PI3K/Akt. These pathways normally promote cell growth and division. However, mutational dysregulation allows them to continue signaling proliferation even when apoptosis should occur or growth signals are absent. Additionally, reduced apoptosis prevents the activation of pro-apoptotic pathways that normally act as brakes on cell division. [Luo \u0026amp; Heng, 2003] Also, healthy cells respond to cues like density-dependent inhibition and nutrient limitations by activating apoptosis. When apoptosis is compromised, cells can evade these growth-inhibitory signals and continue dividing even when resources are limited or cell density is high. This allows the tumor to expand beyond its boundaries and invade surrounding tissues. [Fulda \u0026amp; Debatin, 2007]. A decrease in apoptosis is therefore essential to maintain tumor growth.\u0026nbsp;\u003c/span\u003eHowever, cell proliferation is also an essentiel element in promoting tumor growth.\u0026nbsp;\u003cspan style=\"font-size:12pt\"\u003eYet, due to the presence of diverging evidence on the activation of the AhR and cell proliferation, we chose not to include these in our AOP. Indeed, on one hand, activation of the AhR through ligands such as NK150460, ANI-7, emodine or derivates of revesterol decrease cell proliferation in ER-positive and ER-negative breast cancer cell lines.\u0026nbsp;TCDD has been found to promote cell cycle arrest through phosphorylation of the retinoblastoma protein which binds to E2F. In ER-positive cell lines, beta-naphthoflavone mediated cell cycle arrest through an upregulation of P21.\u0026nbsp;On the other hand, AhR activation could promote cell proliferation. Pearce et al. found that MCDF (6-methyl-1,3,8-trichlorodibenzofuran), an AhR agonist could stimulate cell proliferation with a dose-response concordance.\u0026nbsp;Likewise, I3C, HCB, CPF and licorice could also promote cell proliferation. However, it seems that this cell proliferation is ER-dependent.\u0026nbsp;Indeed, these ligands induced cell proliferation only in ER-positive cells lines with an effect dependent on the level of estrogen present in the medium. Whether this increase in ER-dependent cell proliferation can be independent of the AhR remains unclear.\u0026nbsp;This increase in proliferation could also be mediated by the association of the RelA subunit of NF-kappaB with the AhR resulting in the activation of c-myc gene transcription in breast cancer cells.\u0026nbsp;This would explain why Rodriguez \u003cem\u003eet al\u003c/em\u003e. found that proliferation was modulated by the CYP1A1, independently of an exogenous ligand activation of the AhR. These complex effects, highly dependent on the context (cell types, medium content, type of ligand\u0026hellip;) were therefore not included in our AOP despite the strong evidence. \u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd\u003e\u0026nbsp;\u003c/td\u003e\r\n\t\t\t\u003ctd\u003e\u0026nbsp;\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cstrong\u003eKE 1971\u0026nbsp;:\u0026nbsp; tumor growth\u003c/strong\u003e\u003c/span\u003e\u003c/td\u003e\r\n\t\t\t\u003ctd\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003eSTRONG\u003c/span\u003e\u003c/td\u003e\r\n\t\t\t\u003ctd\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003eAn increase in tumor size is associated with breast cancer metastasis and is essential to the progression of the illness\u0026nbsp;\u0026nbsp;(\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0210\" name=\"bb0210\"\u003eHanahan and Weinberg, 2011 Mar 4\u003c/a\u003e). Indeed, clinical evidence suggests that tumor size is directly correlated to the presence of metastasis (\u003cspan style=\"font-size:12.0pt\"\u003eLiu Y, He M, Zuo WJ, Hao S, Wang ZH, Shao ZM. Tumor Size Still Impacts Prognosis in Breast Cancer With Extensive Nodal Involvement. Front Oncol and Narod SA. Tumour size predicts long-term survival among women with lymph node-positive breast cancer. Curr Oncol.) Likewise, s\u003c/span\u003e\u003c/span\u003etudies have shown that larger tumor size in colorectal cancer is associated with\u0026nbsp;\u003cstrong\u003eincreased risk of metastasis\u003c/strong\u003e\u0026nbsp;and\u0026nbsp;\u003cstrong\u003epoorer overall survival\u003c/strong\u003e. [Benson et al., 2008]\u003c/td\u003e\r\n\t\t\t\u003ctd\u003e\u0026nbsp;\u003c/td\u003e\r\n\t\t\t\u003ctd\u003e\u0026nbsp;\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cstrong\u003eKE 1241\u0026nbsp; Increased cell motility\u0026nbsp;\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003eMODERATE\u003c/span\u003e\u003c/td\u003e\r\n\t\t\t\u003ctd\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003eThe relation between cell migration and organ invasion is essntial.\u0026nbsp;Organ invasion can be promonted by cell migration, motility and inflammation. Therefore the essentilality of cell motility was classified as moderate since other factors can promote organ invasion. For instance, m\u003c/span\u003eelanoma cells are known for their\u0026nbsp;\u003cstrong\u003ehigh migratory potential\u003c/strong\u003e\u003cspan style=\"font-family:-apple-system,BlinkMacSystemFont,\u0026quot;Segoe UI\u0026quot;,Roboto,\u0026quot;Helvetica Neue\u0026quot;,Arial,\u0026quot;Noto Sans\u0026quot;,sans-serif,\u0026quot;Apple Color Emoji\u0026quot;,\u0026quot;Segoe UI Emoji\u0026quot;,\u0026quot;Segoe UI Symbol\u0026quot;,\u0026quot;Noto Color Emoji\u0026quot;; font-size:1rem\"\u003e, allowing them to invade the surrounding dermis and potentially metastasize to distant organs like the brain and lungs. [Clark et al., 2009] Likewise, b\u003c/span\u003ereast cancer cells can\u0026nbsp;\u003cstrong\u003emigrate through the basement membrane\u003c/strong\u003e\u003cspan style=\"font-family:-apple-system,BlinkMacSystemFont,\u0026quot;Segoe UI\u0026quot;,Roboto,\u0026quot;Helvetica Neue\u0026quot;,Arial,\u0026quot;Noto Sans\u0026quot;,sans-serif,\u0026quot;Apple Color Emoji\u0026quot;,\u0026quot;Segoe UI Emoji\u0026quot;,\u0026quot;Segoe UI Symbol\u0026quot;,\u0026quot;Noto Color Emoji\u0026quot;; font-size:1rem\"\u003e\u0026nbsp;and invade surrounding breast tissue, potentially reaching lymph nodes or blood vessels for further dissemination. [Friedl \u0026amp; Weigelin, 2008]\u003c/span\u003e\u003c/td\u003e\r\n\t\t\t\u003ctd\u003e\u0026nbsp;\u003c/td\u003e\r\n\t\t\t\u003ctd\u003e\u0026nbsp;\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cstrong\u003eKE 1196:\u0026nbsp;organ invasion\u0026nbsp;\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003eSTRONG\u003c/span\u003e\u003c/td\u003e\r\n\t\t\t\u003ctd\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003eOrgan invasion is an essential step in promoting breast cancer agressivness and metastasis. Without invasion of the basal membrane, the cancer remains located in an in situ state and does not induce metastasis.\u0026nbsp;\u0026nbsp;\u003c/span\u003ePancreatic cancer cells are notorious for their\u0026nbsp;\u003cstrong\u003einvasive nature\u003c/strong\u003e\u003cspan style=\"font-family:-apple-system,BlinkMacSystemFont,\u0026quot;Segoe UI\u0026quot;,Roboto,\u0026quot;Helvetica Neue\u0026quot;,Arial,\u0026quot;Noto Sans\u0026quot;,sans-serif,\u0026quot;Apple Color Emoji\u0026quot;,\u0026quot;Segoe UI Emoji\u0026quot;,\u0026quot;Segoe UI Symbol\u0026quot;,\u0026quot;Noto Color Emoji\u0026quot;; font-size:1rem\"\u003e. They can invade surrounding tissues like the pancreas, blood vessels, and nerves, increasing the risk of metastasis to the liver, lungs, and bones. [Olive et al., 2009]\u0026nbsp;\u003c/span\u003e\u003cspan style=\"font-family:-apple-system,BlinkMacSystemFont,\u0026quot;Segoe UI\u0026quot;,Roboto,\u0026quot;Helvetica Neue\u0026quot;,Arial,\u0026quot;Noto Sans\u0026quot;,sans-serif,\u0026quot;Apple Color Emoji\u0026quot;,\u0026quot;Segoe UI Emoji\u0026quot;,\u0026quot;Segoe UI Symbol\u0026quot;,\u0026quot;Noto Color Emoji\u0026quot;; font-size:1rem\"\u003eColorectal cancer cells can invade the bowel wall and potentially reach surrounding blood vessels, allowing them to travel to the liver, lungs, and other distant sites. [Fearon \u0026amp; Vogelstein, 1990]\u003c/span\u003e\u003c/td\u003e\r\n\t\t\t\u003ctd\u003e\u0026nbsp;\u003c/td\u003e\r\n\t\t\t\u003ctd\u003e\u0026nbsp;\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cstrong\u003eKE 149\u0026nbsp; Increased inflammation\u0026nbsp;\u003c/strong\u003e\u003c/span\u003e\u003c/td\u003e\r\n\t\t\t\u003ctd\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003eMODERATE\u003c/span\u003e\u003c/td\u003e\r\n\t\t\t\u003ctd\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003eOrgan invasion can be promonted by cell migration, motility and inflammation. Therefore the essentilality of cell motility was classified as moderate since other factors can promote organ invasion.\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003eIn angiogenesis, however, increased inflammation is a key factor. Indeed, inflammation, through the secretion of growth factor promotes the creation of blood vessels (VEGF, IL6, COX).\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd\u003e\u0026nbsp;\u003c/td\u003e\r\n\t\t\t\u003ctd\u003e\u0026nbsp;\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cstrong\u003eKE 1190 Increased endothelial migration\u0026nbsp;\u003c/strong\u003e\u003c/span\u003e\u003c/td\u003e\r\n\t\t\t\u003ctd\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003eSTRONG\u003c/span\u003e\u003c/td\u003e\r\n\t\t\t\u003ctd\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003eEndothelial cell migration is an essential key event in promoting angiogenesis. Extensive data exists on the essentialitty of this step (Franziska van Zijl, Georg Krupitza, Wolfgang Mikulits, Initial steps of metastasis: Cell invasion and endothelial transmigration, Mutation Research/Reviews in Mutation Research, Volume 728, Issues 1\u0026ndash;2, 2011, Pages 23-34, ISSN 1383-5742, https://doi.org/10.1016/j.mrrev.2011.05.002.)\u003c/span\u003e\u003c/td\u003e\r\n\t\t\t\u003ctd\u003e\u0026nbsp;\u003c/td\u003e\r\n\t\t\t\u003ctd\u003e\u0026nbsp;\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cstrong\u003eKE 1213: angiogenesis\u003c/strong\u003e\u003c/span\u003e\u003c/td\u003e\r\n\t\t\t\u003ctd\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003eSTRONG\u003c/span\u003e\u003c/td\u003e\r\n\t\t\t\u003ctd\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003eWithout the creation of new vessels in order to receive nutrients and energy, the cancer cell cannot survive and create metastatis. It is an essential key event and considered as one of the hallmarks of cancer \u0026nbsp;(\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0210\" name=\"bb0210\"\u003eHanahan and Weinberg, 2011 Mar 4\u003c/a\u003e).\u0026nbsp;\u003c/span\u003e\u003c/td\u003e\r\n\t\t\t\u003ctd\u003e\u0026nbsp;\u003c/td\u003e\r\n\t\t\t\u003ctd\u003e\u0026nbsp;\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\u003c/tbody\u003e\r\n\u003c/table\u003e\r\n\r\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\r\n","weight_of_evidence_summary":"\u003cp\u003e\u003cspan style=\"font-size:11.0pt\"\u003e\u003cspan style=\"background-color:white\"\u003e\u003cspan style=\"font-family:\u0026quot;Times New Roman\u0026quot;,serif\"\u003eWhile strong biological plausibility supports the involvement of AhR signaling in several processes relevant to breast cancer progression, the overall pathway remains supported predominantly by mechanistic and correlative data, with limited demonstration of causality through intervention-based approaches such as receptor knockdown, pharmacological inhibition, or gain-of-function models. In addition, quantitative understanding of key event relationships, including dose-response and temporal concordance, remains incomplete. As outlined in OECD guidance for AOP development, such elements are essential to establish a robust causal framework suitable for regulatory application (OECD, 2017; Villeneuve et al., 2014). Furthermore, although in vitro studies provide valuable mechanistic insights, they are not sufficient on their own to support regulatory decision-making, particularly in complex diseases such as cancer where tumor\u0026ndash;host interactions and microenvironmental factors play a critical role. Therefore, either in vivo confirmation or strong evidence demonstrating that in vitro endpoints are predictive of in vivo outcomes is required before such an AOP can be considered for use in regulatory standard setting (Tollefsen et al., 2014; Leist et al., 2017). In this context, the present AOP should be regarded as a qualitative and context-dependent mechanistic framework that integrates existing knowledge and supports hypothesis generation. \u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\u003ch4\u003eKER 2569\u0026nbsp; Activation of the AhR leads to decreased apoptosis\u003c/h4\u003e\r\n\r\n\u003cp\u003eSeveral studies have found that the activation of the AhR by stressors such as TCDD, can promote a decrease in apoptosis (KER2569), which is a deleterious event with regards to cancer (\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0005\" name=\"bb0005\"\u003eAl-Dhfyan et al., 2017 Jan 19\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0035\" name=\"bb0035\"\u003eBekki et al., 2015\u003c/a\u003e). Additionally, an increase in cell death was found when blocking the AhR pathway using AhR silencing (RNA interference or knock-out), knockout cell lines or antagonists (CH223191 or alpha-naphthoflavone) (\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0180\" name=\"bb0180\"\u003eGoode et al., 2013 Dec 15\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0005\" name=\"bb0005\"\u003eAl-Dhfyan et al., 2017 Jan 19\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0035\" name=\"bb0035\"\u003eBekki et al., 2015\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0530\" name=\"bb0530\"\u003eRegan Anderson et al., 2018\u003c/a\u003e). The most frequently used assay to evaluate apoptosis was\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/topics/earth-and-planetary-sciences/cytometry\" title=\"Learn more about cytometry from ScienceDirect's AI-generated Topic Pages\"\u003ecytometry\u003c/a\u003e\u0026nbsp;with the use of Annexin V: this was performed with ER-positive cells lines (MCF-7, T-47D), triple negative cell lines (MDA-MB-231, HS 578), cells over-expressing the Her2 (SK-BR-3) and cells lines derived from cancer samples from patients (\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0180\" name=\"bb0180\"\u003eGoode et al., 2013 Dec 15\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0005\" name=\"bb0005\"\u003eAl-Dhfyan et al., 2017 Jan 19\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0035\" name=\"bb0035\"\u003eBekki et al., 2015\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0530\" name=\"bb0530\"\u003eRegan Anderson et al., 2018\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0145\" name=\"bb0145\"\u003eFujisawa et al., 2011\u003c/a\u003e).\u003c/p\u003e\r\n\r\n\u003cp\u003eThe concordance of the evidence was classified as \u0026ldquo;moderate\u0026rdquo; since the aim of most studies was to evaluate the capacity to survive in an apoptosis-promoting environment (i.e., chemotherapeutic drugs). Indeed, they assessed the resistance to chemotherapy agents such as doxorubicin and paclitaxel and found that the concomitant inactivation of the AhR pathway could decrease the resistance to these chemotherapy agents through an increase in cell death when compared to cells with a functional (or expressed at sufficient levels) AhR (\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0180\" name=\"bb0180\"\u003eGoode et al., 2013 Dec 15\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0005\" name=\"bb0005\"\u003eAl-Dhfyan et al., 2017 Jan 19\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0035\" name=\"bb0035\"\u003eBekki et al., 2015\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0530\" name=\"bb0530\"\u003eRegan Anderson et al., 2018\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0145\" name=\"bb0145\"\u003eFujisawa et al., 2011\u003c/a\u003e). Since the environment was modified by the presence of chemotherapy, the hypothesis of an alternative pathway cannot be completely discarded. It must be noticed that the exact biological mechanisms linking the activation of the AhR to the decrease in apoptosis remains unclear. Indeed, Anderson\u0026nbsp;\u003cem\u003eet al\u003c/em\u003e. suggested that the AhR interacts with the\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/topics/earth-and-planetary-sciences/glucocorticoid\" title=\"Learn more about glucocorticoid from ScienceDirect's AI-generated Topic Pages\"\u003eglucocorticoid\u003c/a\u003e\u0026nbsp;receptor (GR) and the hypoxia inducible factor-2\u0026alpha; (HIF-2\u0026alpha;) (\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0530\" name=\"bb0530\"\u003eRegan Anderson et al., 2018\u003c/a\u003e). The presence of the GR is associated with a poor prognosis, notably in triple negative breast cancer (\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0455\" name=\"bb0455\"\u003ePan et al., 2011\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0420\" name=\"bb0420\"\u003eMoran et al., 2000 Feb 15\u003c/a\u003e). Indeed, this receptor is involved in survival and resistance to chemotherapy through up-regulation of c-myc, Bcl2 and Kruppel-like factor 5 (\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0455\" name=\"bb0455\"\u003ePan et al., 2011\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0685\" name=\"bb0685\"\u003eWu et al., 2004\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0350\" name=\"bb0350\"\u003eLi et al., 2017\u003c/a\u003e). Both GR and HIF 2\u0026alpha; could be up regulated by the AhR. They then activate Brk (also known as PTK6), a ligand of EGFR (epidermal growth factor receptor), involved in the inhibition of apoptosis (\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0530\" name=\"bb0530\"\u003eRegan Anderson et al., 2018\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0355\" name=\"bb0355\"\u003eLi et al., 2012\u003c/a\u003e). Another possible mechanism suggested by Bekki et al. is that the decrease in apoptosis was caused by the induction of cyclooxygenase 2 (COX-2) and the NF-\u0026kappa;B subunit RelB (\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0035\" name=\"bb0035\"\u003eBekki et al., 2015\u003c/a\u003e). They both prevent apoptosis through induction of Bcl2, an anti-apoptotic factor (\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0615\" name=\"bb0615\"\u003eTsujii and DuBois, 1995\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0650\" name=\"bb0650\"\u003eVogel et al., 2007\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0605\" name=\"bb0605\"\u003eThomas et al., 2020\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0025\" name=\"bb0025\"\u003eBaud and Jacque, 2008 Dec\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0110\" name=\"bb0110\"\u003eDemicco et al., 2005 Nov\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0660\" name=\"bb0660\"\u003eWang et al., 2007 Apr\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0375\" name=\"bb0375\"\u003eLiu et al., 2001 May 25\u003c/a\u003e).\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003cstrong\u003eKER 2577: Decreased apoptosis promotes tumor growth\u003c/strong\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003eFor KER 2577,\u0026nbsp;\u003cem\u003ein vivo\u003c/em\u003e, Goode et al. showed that the knockout of the AhR in mice reduced tumor growth through an increase of cell apoptosis (\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0180\" name=\"bb0180\"\u003eGoode et al., 2013 Dec 15\u003c/a\u003e).\u003c/p\u003e\r\n\r\n\u003cp\u003eThe relationship between decreased apoptosis and increase in tumor growth (KER 2577) is not detailed here due to extensive evidence in the scientific literature (\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0210\" name=\"bb0210\"\u003eHanahan and Weinberg, 2011 Mar 4\u003c/a\u003e).\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003cstrong\u003eKER 2570: Activation of the AhR leads to an increased cell motility\u003c/strong\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003eThe activation of the AhR can modulate cell motility in different types of breast cancers such as: ER-positive cells lines (MCF-7, T-47D, ZR-75\u0026ndash;1), triple negative (MDA-MB-231, MDA-MB-435, HS-578-T, SUM149), and cells overexpressing the Her2 (SK-BR-3) (\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0180\" name=\"bb0180\"\u003eGoode et al., 2013 Dec 15\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0530\" name=\"bb0530\"\u003eRegan Anderson et al., 2018\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0460\" name=\"bb0460\"\u003eParks et al., 2014 Nov\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0505\" name=\"bb0505\"\u003ePontillo et al., 2011 Apr\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0525\" name=\"bb0525\"\u003eQin et al., 2011 Oct 20\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0435\" name=\"bb0435\"\u003eNguyen et al., 2016 Nov 15\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0445\" name=\"bb0445\"\u003eNovikov et al., 2016 Nov\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0405\" name=\"bb0405\"\u003eMiret et al., 2016 Jul\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0570\" name=\"bb0570\"\u003eShan et al., 2020 Nov\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0130\" name=\"bb0130\"\u003eDwyer et al., 2021 Feb\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0430\" name=\"bb0430\"\u003eNarasimhan et al., 2018 May 7\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0235\" name=\"bb0235\"\u003eHsieh et al., 2012 Feb\u003c/a\u003e). Activation of the AhR with TCDD, butyl-benzyl\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/topics/earth-and-planetary-sciences/phthalate\" title=\"Learn more about phthalate from ScienceDirect's AI-generated Topic Pages\"\u003ephthalate\u003c/a\u003e, di-n-butyl phthalate, hexachlorobenzene, and benzo[a]pyrene can promote cell migration in different assays (\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0460\" name=\"bb0460\"\u003eParks et al., 2014 Nov\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0505\" name=\"bb0505\"\u003ePontillo et al., 2011 Apr\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0525\" name=\"bb0525\"\u003eQin et al., 2011 Oct 20\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0445\" name=\"bb0445\"\u003eNovikov et al., 2016 Nov\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0405\" name=\"bb0405\"\u003eMiret et al., 2016 Jul\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0570\" name=\"bb0570\"\u003eShan et al., 2020 Nov\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0430\" name=\"bb0430\"\u003eNarasimhan et al., 2018 May 7\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0235\" name=\"bb0235\"\u003eHsieh et al., 2012 Feb\u003c/a\u003e). On the other hand, the use of AhR antagonists, AhR silencing or AhR knockout reversed this effect (\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0180\" name=\"bb0180\"\u003eGoode et al., 2013 Dec 15\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0530\" name=\"bb0530\"\u003eRegan Anderson et al., 2018\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0460\" name=\"bb0460\"\u003eParks et al., 2014 Nov\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0505\" name=\"bb0505\"\u003ePontillo et al., 2011 Apr\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0525\" name=\"bb0525\"\u003eQin et al., 2011 Oct 20\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0445\" name=\"bb0445\"\u003eNovikov et al., 2016 Nov\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0570\" name=\"bb0570\"\u003eShan et al., 2020 Nov\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0430\" name=\"bb0430\"\u003eNarasimhan et al., 2018 May 7\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0235\" name=\"bb0235\"\u003eHsieh et al., 2012 Feb\u003c/a\u003e). The most frequently used assays for evaluating cell migration were the scratch wound assay and the transwell chamber assay. Only three works evaluated the dose\u0026ndash;response concordance of AhR activation with stressors and cell migration (\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0505\" name=\"bb0505\"\u003ePontillo et al., 2011 Apr\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0405\" name=\"bb0405\"\u003eMiret et al., 2016 Jul\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0570\" name=\"bb0570\"\u003eShan et al., 2020 Nov\u003c/a\u003e). The evidence was therefore classified as \u0026ldquo;moderate\u0026rdquo;.\u003c/p\u003e\r\n\r\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eKER 2572: Activation of the AhR leads to an increased invasion\u003c/strong\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003eDue to the extensive robust and concordant literature of the link between activation of the AhR-increased cell motility-increased invasion-breast cancer progression, the confidence in these key events was rated as high. However, due to the use of ligands to activate the AhR, it cannot be completely ruled out that alternative pathways (independent of the AhR) can also contribute to these features. For instance, 2 main pathways seem to explain this increase in migration and invasion: the c-Src/HER1/STAT5b, and ERK1/2\u0026nbsp;pathways. Yet, these pathways seem only to explain the relation between the AhR activation and cell migration / invasion, when the ligand used is hexachlorobenzene, an organochlorinated pesticide (\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0505\" name=\"bb0505\"\u003ePontillo et al., 2011 Apr\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0405\" name=\"bb0405\"\u003eMiret et al., 2016 Jul\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0510\" name=\"bb0510\"\u003ePontillo et al., 2013 May 1\u003c/a\u003e). Even though alternative mechanisms may present themselves, all studies blocked the AhR pathway and found a decrease in cell migration/invasion. The evidence for alternative mechanisms was therefore classified as \u0026ldquo;moderate\u0026rdquo; and the biological plausibility of KER was also classified as \u0026ldquo;moderate\u0026rdquo;.\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003cstrong\u003eKER 1306: Increased cell motility promotes organ invasion\u003c/strong\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003eThe relation between cell migration and organ invasion has already been shown (KER-1306,\u0026nbsp;\u003ca href=\"https://aopwiki.org/relationships/1306\" rel=\"noreferrer noopener\" target=\"_blank\"\u003ehttps://aopwiki.org/relationships/1306\u003c/a\u003e). Since the 2 are closely linked, most articles studied both cell migration (chemo-tactic) and the capacity to invade the extra-cellular matrix. Cell invasion is indeed defined as the capacity of a cell to migrate and degrade/invade the extracellular matrix.\u0026nbsp;\u003cem\u003eIn vitro\u003c/em\u003e, this process was evaluated mostly using transwell chamber with Matrigel\u0026reg; and the presence of matrix metalloproteinases (MMP). This effect was found in ER-positive cells, triple negative cell lines and cells overexpressing the Her2.\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;KER 2572: Activation of the AhR leads to an increased invasion\u003c/strong\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003eThe activation of the AhR through the use of different ligands (benzophenone, butyl benzyl phthalate, di-n-butyl phthalate, hexachlorobenzene,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/topics/earth-and-planetary-sciences/chlorpyrifos\" title=\"Learn more about chlorpyrifos from ScienceDirect's AI-generated Topic Pages\"\u003echlorpyrifos\u003c/a\u003e, TCDD) or the blockage of the AhR (silencing, KO or antagonism) increased or decreased cell invasion, respectively (\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0460\" name=\"bb0460\"\u003eParks et al., 2014 Nov\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0525\" name=\"bb0525\"\u003eQin et al., 2011 Oct 20\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0435\" name=\"bb0435\"\u003eNguyen et al., 2016 Nov 15\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0405\" name=\"bb0405\"\u003eMiret et al., 2016 Jul\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0570\" name=\"bb0570\"\u003eShan et al., 2020 Nov\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0430\" name=\"bb0430\"\u003eNarasimhan et al., 2018 May 7\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0235\" name=\"bb0235\"\u003eHsieh et al., 2012 Feb\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0510\" name=\"bb0510\"\u003ePontillo et al., 2013 May 1\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0400\" name=\"bb0400\"\u003eMiller et al., 2005\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0040\" name=\"bb0040\"\u003eBelguise et al., 2007 Dec 15\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0695\" name=\"bb0695\"\u003eYamashita et al., 2018 May 1\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0410\" name=\"bb0410\"\u003eMiret et al., 2020 May\u003c/a\u003e). The dose\u0026ndash;response concordance for cell invasion was demonstrated using increasing doses of hexachlorobenzene, benzo[a]pyrene, chlorpyrifos and TCDD (\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0405\" name=\"bb0405\"\u003eMiret et al., 2016 Jul\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0570\" name=\"bb0570\"\u003eShan et al., 2020 Nov\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0510\" name=\"bb0510\"\u003ePontillo et al., 2013 May 1\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0400\" name=\"bb0400\"\u003eMiller et al., 2005\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0410\" name=\"bb0410\"\u003eMiret et al., 2020 May\u003c/a\u003e). To further explore cell invasion, Nguyen et al. created a model of a lymphatic barrier using a three-dimensional lymph endothelial cell as a monolayer co-cultured with\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/topics/earth-and-planetary-sciences/spheroid\" title=\"Learn more about spheroids from ScienceDirect's AI-generated Topic Pages\"\u003espheroids\u003c/a\u003e\u0026nbsp;of MDA-MB231 cells (\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0435\" name=\"bb0435\"\u003eNguyen et al., 2016 Nov 15\u003c/a\u003e). They found that silencing or antagonizing the AhR (DIM) or activating the AhR (FICZ) respectively decreased or increased invasion of the lymphatic barrier.\u003c/p\u003e\r\n\r\n\u003cp\u003eOn an organ level,\u0026nbsp;\u003cem\u003ein vivo\u003c/em\u003e, an increase in metastasis has been found in mice and zebrafish after the activation of the AhR with different ligands (butyl benzyl phthalate, di-n-butyl phthalate, hexachlorobenzene, TCDD) (\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0185\" name=\"bb0185\"\u003eGoode et al., 2014\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0570\" name=\"bb0570\"\u003eShan et al., 2020 Nov\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0430\" name=\"bb0430\"\u003eNarasimhan et al., 2018 May 7\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0235\" name=\"bb0235\"\u003eHsieh et al., 2012 Feb\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0510\" name=\"bb0510\"\u003ePontillo et al., 2013 May 1\u003c/a\u003e). In the zebrafish model, Narasimham et al. treated the animals either with triple negative MDA-MB-231 cells only (untreated) or with MDA-MB-231 cells treated with an AhR inhibitor (CB7993113 or CH22319) (\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0430\" name=\"bb0430\"\u003eNarasimhan et al., 2018 May 7\u003c/a\u003e). Untreated fish had significantly more metastasis (OR\u0026nbsp;=\u0026nbsp;9, IC95%=3\u0026ndash;35). Similar results were found using mice models (\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0185\" name=\"bb0185\"\u003eGoode et al., 2014\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0570\" name=\"bb0570\"\u003eShan et al., 2020 Nov\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0430\" name=\"bb0430\"\u003eNarasimhan et al., 2018 May 7\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0235\" name=\"bb0235\"\u003eHsieh et al., 2012 Feb\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0510\" name=\"bb0510\"\u003ePontillo et al., 2013 May 1\u003c/a\u003e).\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003cstrong\u003eKER 2568: Activation of the AhR leads to an increased inflammation\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003eIn triple negative breast cell lines (MDA-MB436, MDA-MB-231) and ER-positive cell lines, it has been shown that the activation of the AhR can lead to an increase in inflammation. (\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0035\" name=\"bb0035\"\u003eBekki et al., 2015\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0400\" name=\"bb0400\"\u003eMiller et al., 2005\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0695\" name=\"bb0695\"\u003eYamashita et al., 2018 May 1\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0105\" name=\"bb0105\"\u003eDegner et al., 2009 Jan\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0655\" name=\"bb0655\"\u003eVogel et al., 2011 Aug 1\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0295\" name=\"bb0295\"\u003eKolasa et al., 2013 Apr 25\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0630\" name=\"bb0630\"\u003eVacher et al., 2018\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0390\" name=\"bb0390\"\u003eMalik et al., 2019 Oct\u003c/a\u003e). The stressors mainly used to activate the AhR were TCDD followed by benzo[a]pyrene and 2-amino-1-methyl-6-phenylimidazo [4, 5-b]\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/topics/earth-and-planetary-sciences/pyridine\" title=\"Learn more about pyridine from ScienceDirect's AI-generated Topic Pages\"\u003epyridine\u003c/a\u003e\u0026nbsp;(PhiP). After AhR inhibition (KO or antagonists), a decrease in inflammation biomarkers was found (\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0400\" name=\"bb0400\"\u003eMiller et al., 2005\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0695\" name=\"bb0695\"\u003eYamashita et al., 2018 May 1\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0105\" name=\"bb0105\"\u003eDegner et al., 2009 Jan\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0655\" name=\"bb0655\"\u003eVogel et al., 2011 Aug 1\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0295\" name=\"bb0295\"\u003eKolasa et al., 2013 Apr 25\u003c/a\u003e). Assays evaluating cell inflammation were quantitative dosages of IL-6, IL-8 and Cox2 activity/expression. Cox-2 and IL-8 were amongst the top \u0026ldquo;gene concepts\u0026rdquo; retrieved by the PubTator Central tool, likewise, \u0026ldquo;inflammation\u0026rdquo; was frequently found as a disease concept. The most consensual pathway linking the AhR activation to cell inflammation was the NF-kB pathway (\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0655\" name=\"bb0655\"\u003eVogel et al., 2011 Aug 1\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0295\" name=\"bb0295\"\u003eKolasa et al., 2013 Apr 25\u003c/a\u003e). Only half of the studies found a dose\u0026ndash;response relationship (\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0400\" name=\"bb0400\"\u003eMiller et al., 2005\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0295\" name=\"bb0295\"\u003eKolasa et al., 2013 Apr 25\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0390\" name=\"bb0390\"\u003eMalik et al., 2019 Oct\u003c/a\u003e). No studies were carried out\u0026nbsp;\u003cem\u003ein vivo\u003c/em\u003e\u0026nbsp;for breast cancer and therefore the concordance and evidence were classified as \u0026ldquo;moderate\u0026rdquo;.\u003c/p\u003e\r\n\r\n\u003cp\u003eAOP 21 also found the association between AhR activation and inflammation\u0026nbsp;\u003cem\u003evia\u003c/em\u003e\u0026nbsp;COX 2 (Aryl hydrocarbon receptor activation leading to early life stage mortality, via increased COX-2) with a weight of evidence classified as \u0026ldquo;high\u0026rdquo;. Indeed, the AhR/ARNT heterodimer links to the dioxin responsive elements which in turn up-regulates COX-2 (66,67].\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;KER 2573: Inflammation promotes organ invasion\u003c/strong\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003eIn the specific setting of AhR activation, only 2 studies showed the continuum between AhR activation \u0026ndash; increased inflammation \u0026ndash; increased invasion (\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0400\" name=\"bb0400\"\u003eMiller et al., 2005\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0695\" name=\"bb0695\"\u003eYamashita et al., 2018 May 1\u003c/a\u003e). However, in general, there is extensive knowledge on the relationship between cell inflammation and organ invasion. First, COX-2 is expressed at higher levels in triple negative invasive breast cancers than in less aggressive ER-positive cancers (\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0175\" name=\"bb0175\"\u003eGilhooly and Rose, 1999 Aug\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0380\" name=\"bb0380\"\u003eLiu and Rose, 1996 Nov 15\u003c/a\u003e). COX-2 catalyzes the conversion of arachidonic acid into\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/topics/earth-and-planetary-sciences/prostaglandin\" title=\"Learn more about prostaglandin from ScienceDirect's AI-generated Topic Pages\"\u003eprostaglandin\u003c/a\u003e\u0026nbsp;H2, a pro-inflammatory factor, and is therefore considered as a prognosis factor in breast cancer (\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0540\" name=\"bb0540\"\u003eRistim\u0026auml;ki et al., 2002 Feb 1\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0465\" name=\"bb0465\"\u003eParrett et al., 1997 Mar\u003c/a\u003e). Transfection with COX-2 triple negative MDA-MB-435 cells increased cell migration 2-fold compared to control cells in a transwell-Matrigel\u0026reg; assay. Antagonism of COX-2 through an inhibitor (NS-398) reversed this action in a dose-dependent way (\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0580\" name=\"bb0580\"\u003eSingh et al., 2005 May\u003c/a\u003e). Second,\u0026nbsp;\u003cem\u003ein vivo\u003c/em\u003e, the use of anti-inflammatory treatments such as celecoxib (COX-2 inhibitor) can reduce tumor growth and spread (\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0215\" name=\"bb0215\"\u003eHarris et al., 2000 Apr 15\u003c/a\u003e). Finally, epidemiologic evidence suggests that inflammatory breast cancers have the worse prognosis. Indeed, the median overall survival of patients with inflammatory breast cancer compared with those with non-inflammatory breast cancer tumors is 4.75\u0026nbsp;years\u0026nbsp;\u003cem\u003eversus\u003c/em\u003e\u0026nbsp;13.40\u0026nbsp;years for stage III disease and 2.27\u0026nbsp;years\u0026nbsp;\u003cem\u003eversus\u003c/em\u003e\u0026nbsp;3.40\u0026nbsp;years for stage IV disease (\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0560\" name=\"bb0560\"\u003eSchlichting et al., 2012 Aug\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0140\" name=\"bb0140\"\u003eFouad et al., 2017 Apr\u003c/a\u003e).\u003c/p\u003e\r\n\r\n\u003cp\u003eThe mechanism of action of COX-2 are consensual. COX-2 promotes cell invasion through upregulation of MMPs (notably 2 and 9) (\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0600\" name=\"bb0600\"\u003eTakahashi et al., 1999 Oct 22\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0585\" name=\"bb0585\"\u003eSivula et al., 2005 Feb\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0340\" name=\"bb0340\"\u003eLarkins et al., 2006 Jul\u003c/a\u003e). Moreover, COX-2 could also activate the urokinase plasminogen activator (uPA) which degrades the basal membrane of epithelia (\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0580\" name=\"bb0580\"\u003eSingh et al., 2005 May\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0600\" name=\"bb0600\"\u003eTakahashi et al., 1999 Oct 22\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0340\" name=\"bb0340\"\u003eLarkins et al., 2006 Jul\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0200\" name=\"bb0200\"\u003eGuyton et al., 2000 Mar\u003c/a\u003e).\u003c/p\u003e\r\n\r\n\u003cp\u003eThe relationship between inflammation and invasion is well document therefore the evidence was classified as \u0026ldquo;strong\u0026rdquo;.\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;KER 2574: Inflammation promotes angiogenesis\u003c/strong\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003eLikewise, two studies evaluated the specific continuum AhR activation \u0026ndash; increased inflammation \u0026ndash; increased\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/topics/earth-and-planetary-sciences/angiogenesis\" title=\"Learn more about angiogenesis from ScienceDirect's AI-generated Topic Pages\"\u003eangiogenesis\u003c/a\u003e\u0026nbsp;(\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0500\" name=\"bb0500\"\u003ePontillo et al., 2015 Nov 19\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0705\" name=\"bb0705\"\u003eZ\u0026aacute;rate et al., 2020 Aug\u003c/a\u003e). As previously mentioned, the AhR activation increases inflammation, notably through an increase in COX 2 (\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0035\" name=\"bb0035\"\u003eBekki et al., 2015\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0400\" name=\"bb0400\"\u003eMiller et al., 2005\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0105\" name=\"bb0105\"\u003eDegner et al., 2009 Jan\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0500\" name=\"bb0500\"\u003ePontillo et al., 2015 Nov 19\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0705\" name=\"bb0705\"\u003eZ\u0026aacute;rate et al., 2020 Aug\u003c/a\u003e).\u003c/p\u003e\r\n\r\n\u003cp\u003eCOX-2 can promote angiogenesis through an increase in VEGF (Vascular endothelial growth factor) (\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0220\" name=\"bb0220\"\u003eHarris et al., 2014 Oct 10\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0290\" name=\"bb0290\"\u003eKirkpatrick et al., 2002\u003c/a\u003e)\u003cem\u003e.\u003c/em\u003e\u0026nbsp;In a pathologic study characterizing 46 breast cancer specimen using immunochemistry, it was found that the density of microvessels was significantly higher in patients with COX-2 expression than in those without expression (p\u0026nbsp;=\u0026nbsp;0.03) (\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0085\" name=\"bb0085\"\u003eCosta et al., 2002 Jun\u003c/a\u003e). The relationship between COX-2 and angiogenesis has also been shown in gastric and colorectal cancer (\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0620\" name=\"bb0620\"\u003eTsujii et al., 1998 May 29\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0625\" name=\"bb0625\"\u003eUefuji et al., 2000 Jan\u003c/a\u003e). Indeed, colon carcinoma cells overexpressing COX-2 produce proangiogenic factors (VEGF, bFGF, TBF-\u0026beta;, PDGF, and endothelin-1), and stimulate endothelial migration and the formation of tube vessels. These effects were reversed by an inhibitor (NS-398).\u0026nbsp;\u003cem\u003eIn vivo\u003c/em\u003e, Diclofenac, a COX-2 inhibitor, decreased angiogenesis in mice presenting a colorectal cancer (\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0565\" name=\"bb0565\"\u003eSeed et al., 1997 May 1\u003c/a\u003e). Likewise, in a murine model of breast cancer, celecoxib (a selective COX-2 inhibitor) reduced metastasis and tumor burden through a decrease of micro vessel density and VEGF (\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0700\" name=\"bb0700\"\u003eYoshinaka et al., 2006 Dec\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0715\" name=\"bb0715\"\u003eZhang et al., 2004 Sep\u003c/a\u003e). In clinical studies, patients with inflammatory breast cancers have increased levels of genes involved in angiogenesis such as VEGF (\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0640\" name=\"bb0640\"\u003eVan der Auwera et al., 2004 Dec 1\u003c/a\u003e). Patients with an inflammatory breast cancer benefit the most from anti-angiogenic treatment bevacizumab (\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0485\" name=\"bb0485\"\u003ePierga et al., 2012 Apr\u003c/a\u003e).\u003c/p\u003e\r\n\r\n\u003cp\u003eThe evidence was classified as \u0026ldquo;moderate\u0026rdquo; due to the lack of dose response studies.\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003cstrong\u003e\u003ca href=\"https://aopwiki.org/relationships\" rel=\"noreferrer noopener\" target=\"_blank\"\u003eKER 1266\u003c/a\u003e: Activation of the AhR leads to an increased endothelial migration\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003eThe activation of the AhR can lead to an increased endothelial cell migration. This was found when HMEC-1 or EA.hy926 cells were co-cultured with ER-positive MCF-7 cells and triple negative MDA-MB-231 cells (\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0500\" name=\"bb0500\"\u003ePontillo et al., 2015 Nov 19\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0705\" name=\"bb0705\"\u003eZ\u0026aacute;rate et al., 2020 Aug\u003c/a\u003e). The assay mainly used was the Matrigel\u0026reg; / tube formation assay. Only one study found an increase in endothelial cell proliferation and not migration, therefore it was not kept as a KE (\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0500\" name=\"bb0500\"\u003ePontillo et al., 2015 Nov 19\u003c/a\u003e). The main pathway explaining this relationship was again related to the activation of COX2 and subsequently to the increase in VEGF. The association between the activation of the AhR and endothelial cell migration was classified as \u0026ldquo;weak\u0026rdquo; since only 2 studies explored this feature, and both used hexachlorobenzene as a stressor. However, these works were robust with strong evidence, and both found a reversed association after AhR blockage. No contradicting results were found in the scientific literature.\u003c/p\u003e\r\n\r\n\u003cp\u003eAs opposed to our work, another AOP displayed a link between AhR activation and angiogenesis (AOP 150) and found that activation of the receptor could decrease VEGF production with moderate evidence and quantitative understanding. It must be noted that these AOPs applied only to chicken, zebrafish, and certain rodents whereas our AOP concerns humans. As detailed further, the AhR presents a variability between species which must be considered.\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003cstrong\u003eKER\u0026nbsp;1267: \u0026nbsp;Increased endothelial migration promotes angiogenesis\u003c/strong\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003ePontillo et al. treated mice with increasing doses of hexachlorobenzene and then calculated the vessel density in mammary fat pads (\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0500\" name=\"bb0500\"\u003ePontillo et al., 2015 Nov 19\u003c/a\u003e). They found that mice treated with hexachlorobenzene had a higher vessel density with a dose\u0026ndash;response concordance. Treatment by AhR antagonists completely reversed this association (\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0500\" name=\"bb0500\"\u003ePontillo et al., 2015 Nov 19\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0705\" name=\"bb0705\"\u003eZ\u0026aacute;rate et al., 2020 Aug\u003c/a\u003e). The relationship between endothelial migration and angiogenesis was not detailed here since there is existing extensive knowledge (\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0325\" name=\"bb0325\"\u003eLamalice et al., 2007 Mar 30\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0440\" name=\"bb0440\"\u003eNorton and Popel, 2016 Nov 14\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0015\" name=\"bb0015\"\u003eAusprunk and Folkman, 1977 Jul 1\u003c/a\u003e). The KER 12 was considered as \u0026ldquo;strong\u0026rdquo;.\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;KER 3137, 3138 and 3137: Increased tumor growth, increased invasion, and increased angiogenesis lead to breast cancer metastasis\u003c/strong\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003eDue to extensive data in the scientific literature and the empirical evidence in favor of these KERs, these KERs were not detailed here.\u003c/p\u003e\r\n","quantitative_considerations":"","optional_considerations":"\u003cp\u003e\u003cspan style=\"font-size:11.0pt\"\u003e\u003cspan style=\"background-color:white\"\u003e\u003cspan style=\"font-family:\u0026quot;Times New Roman\u0026quot;,serif\"\u003eAhR activation is defined as a stressor-agnostic molecular initiating event; however, the downstream biological consequences of this activation are not uniform across ligands. The AhR binds a wide range of structurally diverse ligands, including persistent environmental contaminants such as TCDD and polycyclic aromatic hydrocarbons, as well as endogenous metabolites and dietary compounds. These ligands differ in affinity, metabolic stability, and duration of receptor activation, resulting in distinct transcriptional programs and biological outcomes (Safe et al., 2013; Larigot et al., 2021). In particular, persistent ligands such as TCDD induce sustained AhR activation, whereas endogenous ligands typically trigger transient and sometimes qualitatively different responses. Therefore, although the MIE is defined generically as AhR activation, the present AOP is primarily supported by evidence derived from specific ligand classes and should not be extrapolated to all AhR agonists.\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003cspan style=\"font-size:11.0pt\"\u003e\u003cspan style=\"background-color:white\"\u003e\u003cspan style=\"font-family:\u0026quot;Times New Roman\u0026quot;,serif\"\u003eCurrent evidence linking prototypical AhR ligands to the adverse outcome remains indirect. Experimental studies have shown that exposure to AhR agonists such as TCDD or polycyclic aromatic hydrocarbons can promote pro-metastatic phenotypes in breast cancer models, including increased migration, invasion, and tumor growth. However, no study has demonstrated a complete causal sequence from ligand exposure through all key events to metastatic breast cancer in vivo. 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Current Pharmaceutical Design, 9(21), 1803-1816.\u0026nbsp;\u003ca href=\"https://pubmed.ncbi.nlm.nih.gov/14574468/\" rel=\"noopener noreferrer\" target=\"_blank\"\u003ehttps://pubmed.ncbi.nlm.nih.gov/14574468/\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003eSchmitt, C. A., et al. (2000). Senescence and apoptosis. Oncogene, 19(56), 6207-6210.\u0026nbsp;\u003ca href=\"https://pubmed.ncbi.nlm.nih.gov/11101894/\" rel=\"noopener noreferrer\" target=\"_blank\"\u003ehttps://pubmed.ncbi.nlm.nih.gov/11101894/\u003c/a\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003cspan style=\"font-size:12pt\"\u003e\u003cspan style=\"background-color:white\"\u003e\u003cspan style=\"font-family:\u0026quot;Times New Roman\u0026quot;,serif\"\u003e\u003cspan style=\"font-family:\u0026quot;Helvetica Neue\u0026quot;\"\u003e\u003cspan style=\"color:#1f1f1f\"\u003eBenson, A. B., et al. (2008). Tumor size and stage in colon and rectal cancer: Consistent prognostic factors over time. Annals of Surgery, 247(3), 421-429. \u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003cspan style=\"font-size:12pt\"\u003e\u003cspan style=\"background-color:white\"\u003e\u003cspan style=\"font-family:\u0026quot;Times New Roman\u0026quot;,serif\"\u003e\u003cspan style=\"font-family:\u0026quot;Helvetica Neue\u0026quot;\"\u003e\u003cspan style=\"color:#1f1f1f\"\u003eClark, B. A., et al. (2009). New insights into the biology of human malignant melanoma. Annual Review of Medicine, 60, 361-377.\u0026nbsp;\u003ca href=\"https://pubmed.ncbi.nlm.nih.gov/19021562/\" style=\"color:var(--bard-color-primary); text-decoration:underline\" target=\"_blank\"\u003ehttps://pubmed.ncbi.nlm.nih.gov/19021562/\u003c/a\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003cspan style=\"font-size:12pt\"\u003e\u003cspan style=\"background-color:white\"\u003e\u003cspan style=\"font-family:\u0026quot;Times New Roman\u0026quot;,serif\"\u003e\u003cspan style=\"font-family:\u0026quot;Helvetica Neue\u0026quot;\"\u003e\u003cspan style=\"color:#1f1f1f\"\u003eFriedl, P., \u0026amp; Weigelin, B. (2008. Interstitial cell migration and invasion in cancer and metastasis. Nature Reviews Cancer, 8(10), 700-710.\u0026nbsp;\u003ca href=\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2724717/\" style=\"color:var(--bard-color-primary); text-decoration:underline\" target=\"_blank\"\u003ehttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2724717/\u003c/a\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003cspan style=\"font-size:12pt\"\u003e\u003cspan style=\"background-color:white\"\u003e\u003cspan style=\"font-family:\u0026quot;Times New Roman\u0026quot;,serif\"\u003e\u003cspan style=\"font-family:\u0026quot;Helvetica Neue\u0026quot;\"\u003e\u003cspan style=\"color:#1f1f1f\"\u003eFearon, E. R., \u0026amp; Vogelstein, B. (1990). A genetic model for colorectal tumorigenesis. Cell, 61(5), 759-767.\u0026nbsp;\u003ca href=\"https://pubmed.ncbi.nlm.nih.gov/2202721/\" style=\"color:var(--bard-color-primary); text-decoration:underline\" target=\"_blank\"\u003ehttps://pubmed.ncbi.nlm.nih.gov/2202721/\u003c/a\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003cspan style=\"font-size:12pt\"\u003e\u003cspan style=\"background-color:white\"\u003e\u003cspan style=\"font-family:\u0026quot;Times New Roman\u0026quot;,serif\"\u003e\u003cspan style=\"font-family:\u0026quot;Helvetica Neue\u0026quot;\"\u003e\u003cspan style=\"color:#1f1f1f\"\u003eOlive, P. L., et al. (2009. Inhibition of Hedgehog signaling enhances sensitivity of pancreatic cancer cells to gemcitabine. Clinical Cancer Research, 15(8), 2553-2562.\u0026nbsp;\u003ca href=\"https://pubmed.ncbi.nlm.nih.gov/19318265/\" style=\"color:var(--bard-color-primary); text-decoration:underline\" target=\"_blank\"\u003ehttps://pubmed.ncbi.nlm.nih.gov/19318265/\u003c/a\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n","overall_assessment":"\u003cp\u003eThe\u0026nbsp;\u003cem\u003ebiological plausibility\u003c/em\u003e\u0026nbsp;of KERs is defined by the OECD as the \u0026laquo; understanding of the fundamental biological processes involved and whether they are consistent with the causal relationship being proposed in the AOP \u0026raquo;. The biological plausibility is strong due to the presence of overwhelming evidence present in different studies. A minor setback would be the difficulty to dismiss alternative mechanisms caused by the ligands used for AhR activation. This is detailed in the discussion.\u003c/p\u003e\r\n\r\n\u003cp\u003eThe\u0026nbsp;\u003cem\u003eessentiality of KEs\u003c/em\u003e\u0026nbsp;refers to \u0026laquo;\u0026nbsp;experimental data for whether or not downstream KEs or the AO are prevented or modified if an upstream event is blocked\u0026nbsp;\u0026raquo;. The essentiality of KEs is strong: most works use suppression or inhibition of the AhR (knock out, antagonists and/or silencing) with results coherent with our findings.\u003c/p\u003e\r\n\r\n\u003cp\u003eFinally, the\u0026nbsp;\u003cem\u003eempirical support\u003c/em\u003e\u0026nbsp;of KERs, is often \u0026laquo;\u0026nbsp;based on toxicological data derived by one or more reference chemicals where dose\u0026ndash;response and temporal concordance for the KE pair can be assessed\u0026nbsp;\u0026raquo;. The overall assessment of the empirical support of our KERs is also strong. There is evidence in human cell lines and mice showing a dose\u0026ndash;response and temporal concordance for severity of our KE and the presence of metastasis.\u003c/p\u003e\r\n\r\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12pt\"\u003eWe propose a simple and robust AOP associating activation of the AhR and breast cancer related death through migration, invasion, inflammation, and neo-angiogenesis. \u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12pt\"\u003eOne of the main limitations of our AOP is the existence of these diverse ligands and pathways, complexifying the definition of \u0026lsquo;AhR activation\u0026rsquo; (6,54). Using PubTator, we found that TCDD was by far the most used chemical followed by I3C, alpha-naphthoflavone, polycyclic aromatic hydrocarbons and hexachlorobenzene, all ligands of the AhR. These ligands can activate different pathways after AhR binding and we therefore assumed that these compounds were AhR agonists. It can be difficult to dismiss alternative mechanisms caused by the ligands used for AhR activation. However, the AhR is the only characterized target of TCDD for example, and studies which use several ligands including TCDD, display similar results using the other modulators. Moreover, the concordance of studies using various ligands and the coherence with the AhR inhibition are in favor of the robustness of the proposed AOP. Indeed, to obtain the most accurate AOP possible, the KEs selected had to be present, no matter the ligand used by the study. \u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12pt\"\u003eAnother minor setback of using the AhR, is that the dose response concordance is a non-monotonous curve for several ligands (122,123). Therefore, the tailored Bradford-Hill criteria could sometimes not be fulfilled. \u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12pt\"\u003eMoreover, the originality of our work lies in the use of artificial intelligence too such as AOP-helpfinder, which enables a thoroughly search of existing knowledge in the PubMed database and PubTator (19\u0026ndash;21). Therefore, our literature review was complete and evidence in favor of our proposed AOP was overwhelming. We plan to validate our proposed AOP in a quantitative \u003cem\u003ein vitro\u003c/em\u003e work using Integrated Approaches to Testing and Assessment (IATA).\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n","background":"\u003cp\u003eBreast cancer is a frequent disease, responsible of 2\u0026nbsp;262 419 new cases and 684 996 deaths in 2020 in the world, making it the deadliest female cancer (\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0045\" name=\"bb0045\"\u003eBray et al., 2018\u003c/a\u003e). In 70% of cases, the disease is localized, and the prognosis is favorable with a 5-year survival of 99%. However, once the disease spreads (lymph nodes, metastasis), survival is severely altered with a 5-year survival rate of 26% in case of metastasis (\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0225\" name=\"bb0225\"\u003eHenley et al., 2020\u003c/a\u003e). It is therefore of paramount importance to understand the mechanisms of metastasis in breast cancer.\u003c/p\u003e\r\n\r\n\u003cp\u003eAmongst risk factors clearly established, including obesity, genetic mutations and hormonal exposure, the importance of the role of the environment is currently emerging (\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0315\" name=\"bb0315\"\u003eKoual et al., 2020 Nov 17\u003c/a\u003e). In an epidemiologic study, we found a positive association between the concentrations of 2.3.7.8-TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxine) in the\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/topics/earth-and-planetary-sciences/adipose-tissue\" title=\"Learn more about adipose tissue from ScienceDirect's AI-generated Topic Pages\"\u003eadipose tissue\u003c/a\u003e\u0026nbsp;surrounding the tumors, and breast cancer metastasis in overweight and obese patients (\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0310\" name=\"bb0310\"\u003eKoual et al., 2019\u003c/a\u003e). Moreover, we have shown that, using both\u0026nbsp;\u003cem\u003ein vivo\u003c/em\u003e\u0026nbsp;and\u0026nbsp;\u003cem\u003ein vitro\u003c/em\u003e\u0026nbsp;models,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/topics/earth-and-planetary-sciences/tcdd\" title=\"Learn more about TCDD from ScienceDirect's AI-generated Topic Pages\"\u003eTCDD\u003c/a\u003e\u0026nbsp;exposure could promote an aggressive phenotype to breast cancer cells, thus favoring the formation of metastatic cells (\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0320\" name=\"bb0320\"\u003eKoual et al., 2021\u003c/a\u003e). TCDD is a potent ligand of the aryl hydrocarbon receptor (AhR), a transcriptional factor involved notably in the metabolism of\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/topics/earth-and-planetary-sciences/xenobiotic\" title=\"Learn more about xenobiotics from ScienceDirect's AI-generated Topic Pages\"\u003exenobiotics\u003c/a\u003e\u0026nbsp;(\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0335\" name=\"bb0335\"\u003eLarigot et al., 2022\u003c/a\u003e). Hence, the impact of the environment on breast cancer aggressiveness could be mediated by the activation of the AhR.\u003c/p\u003e\r\n\r\n\u003cp\u003eInterest is growing on the role of the AhR in breast cancer. First, the AhR is often overexpressed in different breast cancer cell lines (\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0730\" name=\"bb0730\"\u003eZudaire et al., 2008\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0285\" name=\"bb0285\"\u003eKim et al., 2000 Nov 16\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0360\" name=\"bb0360\"\u003eLi et al., 2014\u003c/a\u003e). Interestingly, the level of expression can be correlated to the stage or the molecular sub-type of the disease (\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0730\" name=\"bb0730\"\u003eZudaire et al., 2008\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0725\" name=\"bb0725\"\u003eZhao et al., 2013\u003c/a\u003e). Second, the AhR pathway has been associated with different pro-metastatic features in breast cancer, such as resistance to apoptosis,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/topics/earth-and-planetary-sciences/invasiveness\" title=\"Learn more about invasiveness from ScienceDirect's AI-generated Topic Pages\"\u003einvasiveness\u003c/a\u003e, modified cell cycle, migration and proliferation (\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0730\" name=\"bb0730\"\u003eZudaire et al., 2008\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0180\" name=\"bb0180\"\u003eGoode et al., 2013 Dec 15\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0275\" name=\"bb0275\"\u003eKanno et al., 2006\u003c/a\u003e). Triple negative cell lines, breast cancer cell lines with the worse prognosis (not over-expressing Her2 receptor or hormonal receptors), over-expressing the AhR seem to develop stem-like characteristics, favoring epithelial-mesenchymal transition (EMT) and thus metastasis (\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0590\" name=\"bb0590\"\u003eStanford et al., 2016\u003c/a\u003e). Thirdly, the AhR could be involved in the resistance of breast cancer to treatments (\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0180\" name=\"bb0180\"\u003eGoode et al., 2013 Dec 15\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0185\" name=\"bb0185\"\u003eGoode et al., 2014\u003c/a\u003e): after AhR knockout, Goode\u0026nbsp;\u003cem\u003eet al.\u003c/em\u003e\u0026nbsp;found enhanced sensitivity of paclitaxel (a drug targeting cancer cells) in triple negative breast cancer, a cancer particularly difficult to treat (\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0185\" name=\"bb0185\"\u003eGoode et al., 2014\u003c/a\u003e). Breast cancer patients expressing estrogen receptors (ER-positive) in their cancer cells, can benefit from an efficient endocrine therapy, which greatly improves their survival. Activation of the AhR can lead to the loss of expression of the ER alpha and therefore to the loss of a potential therapeutic target (\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0555\" name=\"bb0555\"\u003eSafe et al., 2000 Jul\u003c/a\u003e).\u003c/p\u003e\r\n\r\n\u003cp\u003eThe mechanisms linking the activation of the AhR to breast cancer aggressiveness are still unclear. Based on the AOP-wiki database (\u003ca href=\"https://aopwiki.org/\" rel=\"noreferrer noopener\" target=\"_blank\"\u003e\u003cu\u003ehttps://aopwiki.org/\u003c/u\u003e\u003c/a\u003e, last accessed March 2022), the central repository for AOPs, the AhR has already been proposed in several AOPs, but never in one characterized by the AO breast cancer metastasis. Likewise, an AOP linking an MIE to breast cancer aggressiveness has never been proposed. From our expertise and available knowledge, we hypothesize that the activation of the AhR could be a MIE leading to breast cancer metastasis (AO) through different KEs and KERs.\u003c/p\u003e\r\n","user_defined_mie":null,"user_defined_ao":null,"oecd_project":"1.105","oecd_status_id":3,"graphical_representation_image_uid":"2024/03/05/9ety9sxdko_Screenshot_2024_03_05_at_15.03.13.png","saaop_status_id":1,"legacy":false,"overall_assessment_file_uid":null,"changed_at":"2026-03-31T13:09:10.000-04:00","development_strategy":"\u003ch3\u003e1.\u0026nbsp;Data input, automatic identification, and extraction of the available knowledge\u003c/h3\u003e\r\n\r\n\u003cp\u003eAn artificial intelligence based method, named AOP-helpFinder (\u003ca href=\"https://aop-helpfinder.u-paris-sciences.fr/index.php\" rel=\"noreferrer noopener\" target=\"_blank\"\u003ehttps://aop-helpfinder.u-paris-sciences.fr/index.php\u003c/a\u003e), was used to scope the available relevant literature (\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0055\" name=\"bb0055\"\u003eCarvaillo et al., 2019\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0710\" name=\"bb0710\"\u003eZgheib et al., 2021\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0550\" name=\"bb0550\"\u003eRugard et al., 2020 Jan 1\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0260\" name=\"bb0260\"\u003eJornod et al., 2020\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0265\" name=\"bb0265\"\u003eJornod et al., 2022\u003c/a\u003e). This tool screens the contents of abstracts from the PubMed database using lists of key words, including stressors, MIEs, KEs and AOs. It then automatically finds, and extracts links co-mentioned in abstracts between pairs of events (MIE/KE/AO) and ranks them using graph theory. In the proposed study, the key words included MIEs (AhR \u0026hellip;), KEs (migration, hypoxia, colony\u0026hellip;) and an AO (breast cancer, mammary tumor\u0026hellip;). All biological events used for the screening were defined using AOP-wiki database and personal keywords. We first scanned the list of KE and KER proposed by AOP wiki and retained words and concepts which concerned cancer aggressivity. Personal keywords were added if necessary (ex: EMT). We reviewed the list of words as a team in order to be as extensive as possible. The key words used can be found in Supplementary Table S1.\u003c/p\u003e\r\n\r\n\u003cp\u003eThe obtained results (i.e., abstracts co-mentioning KE and AO) were manually curated to refine them, and keep the most significant knowledge. First only the abstracts were read and if the article was kept, the full text was reviewed. A manual curation decision tree was created to only include articles that concerned: i) the AhR, ii) breast cancer, iii) cancer progression and not initiation and iv) reviews were excluded (details in results \u0026sect;1 AOP-helpFinder text mining tool).\u003c/p\u003e\r\n\r\n\u003cp\u003eThe newly established version of the AOP-helpFinder tool was applied on the more than 30 million available abstracts from PubMed database, which allowed us to use the two proposed options: i) the refinement filter based on machine learning method (lemmatization process of text) combined with deletion of words of context in order to improve the accuracy of the outputs, and ii) the reduced search option which allow to screen only a part of the abstracts (\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0265\" name=\"bb0265\"\u003eJornod et al., 2022\u003c/a\u003e). This allows to not screen the introductory part of an abstract which usually refer to a study hypothesis, with the aim to decrease false positives.\u003c/p\u003e\r\n\r\n\u003cp\u003eIn order to cross-check the selected concepts, and to support the evidence in favor of the proposed AOP, all selected articles (after text mining and manual curation) were run through the PubTator Central tool (\u003ca href=\"https://www.ncbi.nlm.nih.gov/research/pubtator/\" rel=\"noreferrer noopener\" target=\"_blank\"\u003ehttps://www.ncbi.nlm.nih.gov/research/pubtator/\u003c/a\u003e). PubTator is a web-based system that screens PubMed abstracts and PMC full-text articles for biomedical concepts (genes, diseases, mutations, species, cell lines) (\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0680\" name=\"bb0680\"\u003eWei et al., 2013\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0675\" name=\"bb0675\"\u003eWei et al., 2019 Jul 2\u003c/a\u003e). The PMIDs of the selected articles were used, and PubTator scanned their abstracts. The system overview is detailed by Wei et al. here (\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0675\" name=\"bb0675\"\u003eWei et al., 2019 Jul 2\u003c/a\u003e). The retrieved chemical, disease, species, cell line and gene concepts were used to support the developed AOP.\u003c/p\u003e\r\n\r\n\u003ch3\u003e2.\u0026nbsp;AOP \u0026ndash; Knowledge integration and weight of evidence assessment\u003c/h3\u003e\r\n\r\n\u003cp\u003eThe AOP was then developed using all the previously extracted data, using the \u003cspan style=\"font-size:12.0pt\"\u003e\u003cspan style=\"font-family:\u0026quot;Arial\u0026quot;,sans-serif\"\u003eAOP developers\u0026rsquo; handbook\u003c/span\u003e\u003c/span\u003e (\u003cspan style=\"font-size:12.0pt\"\u003e\u003cspan style=\"font-family:\u0026quot;Arial\u0026quot;,sans-serif\"\u003e\u003ca href=\"https://aopwiki.org/handbooks/\" style=\"color:blue; text-decoration:underline\"\u003ehttps://aopwiki.org/handbooks/\u003c/a\u003e\u003c/span\u003e\u003c/span\u003e). The graphical linear flow diagram was used to represent our proposed AOP.\u003c/p\u003e\r\n\r\n\u003cp\u003eThe evidence supporting the AOP was organized and evaluated according to the tailored Bradford-Hill criteria, as described by \u003cspan style=\"font-size:12.0pt\"\u003e\u003cspan style=\"font-family:\u0026quot;Arial\u0026quot;,sans-serif\"\u003eAOP developers\u0026rsquo; handbook\u003c/span\u003e\u003c/span\u003e (\u003cspan style=\"font-size:12.0pt\"\u003e\u003cspan style=\"font-family:\u0026quot;Arial\u0026quot;,sans-serif\"\u003e\u003ca href=\"https://aopwiki.org/handbooks/\" style=\"color:blue; text-decoration:underline\"\u003ehttps://aopwiki.org/handbooks/\u003c/a\u003e\u003c/span\u003e\u003c/span\u003e) and OECD guidance (\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0450\" name=\"bb0450\"\u003eOECD, 2018\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0230\" name=\"bb0230\"\u003eHill, 1965\u003c/a\u003e). Briefly, these criteria are a group of minimal conditions for providing adequate evidence of a causal relationship between 2 events.\u003c/p\u003e\r\n\r\n\u003cp\u003eFirst, the OECD guidelines were used to evaluate the weight of evidence (WoE) between each KE. The biological applicability domain of each KE was assessed for sex, life stage and taxa. Due to the heterogeneity of breast cancer, another category was added, namely whether the KE is present only in certain types of cancer (ER-positive, triple negative, Her2 overexpression). The types of assays used to measure the KE were also recorded. Then, the confidence in the essentiality of each KE was evaluated using the system proposed by the OECD (high, moderate, low) and detailed in the guidebook.\u003c/p\u003e\r\n\r\n\u003cp\u003eSecond, the tailored Bradford-Hill criteria modified to fit the AOP evidence assessment were used as proposed previously to evaluate each KER (\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0645\" name=\"bb0645\"\u003eVinken et al., 2013\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/science/article/pii/S0160412022002501?via%3Dihub#b0030\" name=\"bb0030\"\u003eBecker et al., 2015\u003c/a\u003e): i) the concordance of dose\u0026ndash;response relationships (ex: is there more migration with higher dosage AhR activators?), ii) the temporal concordance among the KER and AO (ex: is there cell migration before activation of the AhR?), iii) strength, consistency, and specificity of association (ex: use of specific AhR antagonists, silencing or knock out), iv) biological plausibility, coherence, and consistency of the experimental evidence (ex: number of studies finding the association, concordance amongst cell lines), and v) alternative mechanisms that logically present themselves and the extent to which they may distract from the postulated AOP (ex: use of different stressors).\u003c/p\u003e\r\n\r\n\u003cp\u003eThird, the OECD guidelines were used to evaluate the KERs: i) biological plausibility (mechanistic approach), ii) empirical support (dependent change and the experimental data present), iii) evidence and finally iv) quantitative evidence (closely linked to the tailored Bradford-Hill criteria). These were evaluated using the system proposed by the OECD (high, moderate, low) and detailed in the guidebook.\u003c/p\u003e\r\n\r\n\u003cp\u003eFinally, the AOP was overall assessed using the three primary considerations: the biological plausibility, the essentiality of each KE and the empirical support of KERs. Since the detail of the evaluation of the overall weight assessment of the AOP is not described in the OECD guidebook, this evaluation was subjective and decided by our team using all the different elements studied before.\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003cstrong\u003e3.Results\u003c/strong\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0pt\"\u003eA total of 17,760 articles related to the MIE, AhR or aryl hydrocarbon receptor, were identified in the PubMed database (as of December 2021). This list of AhR-related abstracts was used to screen the ones concerning the putative AOP. All abstracts had to mention at least one event from the AO list (breast cancer or synonym) \u003cem\u003eand\u003c/em\u003e one event from the KE list (KEs leading to metastasis: invasion, stemness\u0026hellip;). The list of key words used for searching AOs and KEs can be found in Supplementary Table 1. After merging the identified abstract using their PubMed identifications (PMID), only 407 abstracts were kept from the AhR list with \u003cem\u003eboth\u003c/em\u003e a key event from our AO list and our KE list \u003c/span\u003e\u003cspan style=\"font-size:12.0pt\"\u003eA total of 17,760 articles related to the MIE, AhR or aryl hydrocarbon receptor, were identified in the PubMed database (as of December 2021). This list of AhR-related abstracts was used to screen the ones concerning the putative AOP. All abstracts had to mention at least one event from the AO list (breast cancer or synonym) \u003cem\u003eand\u003c/em\u003e one event from the KE list (KEs leading to metastasis: invasion, stemness\u0026hellip;). The list of key words used for searching AOs and KEs can be found in Supplementary Table 1. After merging the identified abstract using their PubMed identifications (PMID), only 407 abstracts were kept from the AhR list with \u003cem\u003eboth\u003c/em\u003e a key event from our AO list and our KE list \u003c/span\u003e.\u003c/span\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0pt\"\u003eFour steps were used for the manual curation, that was performed by several experts. First, all the abstracts were screened to check if it indeed concerned the AhR. One hundred and thirty-four abstracts were excluded mainly because the retrieved \u0026ldquo;ahr\u0026rdquo; do not concern the aryl hydrocarbon receptor but the adjusted hazards ratio. Moreover, \u0026ldquo;ahr\u0026rdquo; sometimes referred to the last name of an author (Ex: Andre Ahr). Then, only abstracts concerning breast cancer were included. Eighteen abstracts were excluded because they did not directly concern breast cancer. One hundred and nine articles were not selected because they concerned breast cancer initiation and not aggressiveness / metastasis. Finally, 33 articles were reviews and not original works. In total, 113 articles were considered to develop our AOP.\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0pt\"\u003eThe 113 articles were then classified by category in the metastatic process (migration, invasion\u0026hellip;). Each category represented a hallmark of cancer and was associated with the corresponding key words that were used to explore Pubmed using AOP-helpFinder. \u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12pt\"\u003eThe 113 articles were also run through the PubTator Central tool to screen for biomedical concepts. The most frequently found disease was breast cancer, followed by toxicity and concepts concerning metastasis and aggressivity. TCDD (or dioxin, or 2,3,7,8-tetrachlorodibenzo-p-dioxin) was by far the most used chemical followed by estrogen, indole-3-carbinol, alpha-naphthoflavone, polycyclic aromatic hydrocarbons and hexachlorobenzene, mainly ligands of the AhR. Most identified studies concerned humans or mice, except one on zebrafish. The ER-positive cell line MCF-7 was the most frequently studied, followed by the aggressive MDA-MB-231 (triple negative) cell line. Without surprise, the AhR was the \u0026ldquo;gene concept\u0026rdquo; the most assessed followed by the estrogen receptor, CYP1A1 and CYP1B1. All results are displayed in Supplementary data S2. These results guided the concepts used in our AOP and the biological \u003cspan style=\"background-color:white\"\u003e\u003cspan style=\"color:#222222\"\u003eapplicability domain\u003c/span\u003e\u003c/span\u003e. \u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0pt\"\u003eAfter a careful read of the selected articles by all experts and based on their expertise, an adverse outcome network (AON) using 6 different linear AOPs \u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\r\n","known_modulating_factors":"\u003cdiv\u003e\r\n\u003ctable class=\"table table-bordered table-fullwidth\"\u003e\r\n\t\u003cthead\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003cth\u003eModulating Factor (MF)\u003c/th\u003e\r\n\t\t\t\u003cth\u003eInfluence or Outcome\u003c/th\u003e\r\n\t\t\t\u003cth\u003eKER(s) involved\u003c/th\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\u003c/thead\u003e\r\n\t\u003ctbody\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd\u003e\u0026nbsp;\u003c/td\u003e\r\n\t\t\t\u003ctd\u003e\u0026nbsp;\u003c/td\u003e\r\n\t\t\t\u003ctd\u003e\u0026nbsp;\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\u003c/tbody\u003e\r\n\u003c/table\u003e\r\n\u003c/div\u003e\r\n","assigned_license_id":385,"handbook_id":2,"project_129":false},{"id":443,"title":" DNA damage and mutations leading to Metastatic Breast Cancer","short_name":"DNA damage and metastatic breast  cancer","corresponding_author_id":9118,"abstract":"\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:11pt\"\u003e\u003cspan style=\"font-size:12.0pt\"\u003eThis adverse outcome pathway details the effect of alcohol as a stressor in metastatic breast cancer. Aim of this AOP is intended to detail the linkage between alcohol and miRNA- SIRT-1 axis induced metastatic breast cancer which represents a knowledge gap as there are not many references available. Consecutive KEs identified are as follows.\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:11pt\"\u003e\u003cspan style=\"font-size:12.0pt\"\u003eAcetaldehyde, which is a metabolite of alcohol is considered a major mutagen which has been determined to induce genotoxic effects on DNA \u0026nbsp;resulting in increased DNA damage. Inadequate DNA crosslink repair mechanisms leads to accumulation of damaged DNA resulting in impaired DNA synthesis leading to mutations and increased miRNA expression ; leads to disruption of \u0026nbsp;SIRT-1 signalling . This step is followed by increased acetylation and activity of \u0026nbsp;NFkB ; \u0026nbsp;loss of estrogen receptor functions \u0026nbsp;; molecular alterations of epithelial cells ; gain of mesenchymal cell features ; eventuating in increased invasion and migration of breast cancer cells resulting in Metastatic breast cancer .\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n","created_at":"2022-03-21T00:52:30.000-04:00","updated_at":"2024-04-06T12:46:09.000-04:00","status_id":5,"authors":"\u003cp\u003e\u003cstrong\u003eDr Usha S Adiga\u003c/strong\u003e MD PhD, Professor,Department of Biochemistry,Apollo Institute of Medical Sciences \u0026amp;Research,India\u003c/p\u003e\r\n\r\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\r\n\r\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\r\n","applicability_of_the_aop":"\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cstrong\u003eSex\u003c/strong\u003e:The AOP is appicable to women.However s\u003cspan style=\"font-size:11pt\"\u003e\u003cspan style=\"background-color:white\"\u003e\u003cspan style=\"color:#212121\"\u003etudy suggests that the relative risk of breast cancer in men is comparable to that in women for alcohol intakes below 60 g per day. It continues to increase at high consumption levels not usually studied in women (Gu\u0026eacute;nel P et al 2004).\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\r\n\r\n\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cstrong\u003eLife stage:\u003c/strong\u003e\u003cspan style=\"font-size:11pt\"\u003eThere are no research articles which highlight the role alcohol in a particular life stage.\u003c/span\u003e\u003cspan style=\"font-size:11pt\"\u003eIn addition, age-related differences in response to alcohol exposure are neither uniform nor linear. The data available is insufficient which direct the construction of a catalog of \u0026ldquo;appropriate\u0026rdquo; tests or to define all the factors which influence nonlinear effects (\u003cspan style=\"font-size:10.0pt\"\u003e\u003cspan style=\"background-color:white\"\u003e\u003cspan style=\"color:#303030\"\u003eSqueglia LM\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u0026nbsp; et al 2014). \u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cstrong\u003eTaxonomic\u003c/strong\u003e:The evidences for the key events of this AOP are available in various species ike rat,mice and humans.\u003c/span\u003e\u003c/p\u003e\r\n","key_event_essentiality":"\u003cp style=\"text-align:justify\"\u003eDirect evidence is available for all the suggested key events. However the strength of weight of evidence varies from moderate to high. however, some inconsistencies are also available. majority of the experimental evidence is available in rats, mice, canine and human cell lines. only a few studies are available on human subjects.\u003c/p\u003e\r\n\r\n\u003cul\u003e\r\n\t\u003cli style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"color:#212529\"\u003eHuman normal hepatocytes (HL-7702) were subjected to escalating doses of N,N-dimethylformamide for 24 hours (C. Wang et al., 2016).\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"color:#212529\"\u003eAt all concentrations, a concentration-dependent increase in ROS was detected; the rise was statistically significant when compared to control (6.4, 16, 40, 100 mM). Until the highest two concentrations (40 and 100 mM), no significant rise in 8-oxodG was seen, indicating inadequate repair at these dosages.\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"color:#212529\"\u003eExcision repair genes (XRCC2 and XRCC3) were considerably up-regulated at 6.4 and 16 mM, well below the doses that significantly produced 8-oxodG, indicating that adequate DNA repair was possible at these low concentrations. These findings show that repair is competent at low concentrations (removing 8-oxodG quickly), but that repair is swamped (i.e., insufficient) at larger doses, where 8-oxodG greatly increases.\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"color:#212529\"\u003eAS52 Chinese hamster ovary cells (wild type and OGG1-overexpressing) were exposed to varying doses of ultraviolet A (UVA) radiation (Dahle et al., 2008).\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"color:#212529\"\u003eFormamidopyrimidine glycosylase (Fpg)-sensitive sites were quantified using alkaline elution after increasing repair times (0, 1, 2, 3, 4 h) following 100 kJ/m\u003c/span\u003e\u003c/span\u003e\u003csup\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"color:#212529\"\u003e2\u003c/span\u003e\u003c/span\u003e\u003c/sup\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"color:#212529\"\u003e\u0026nbsp;UVA irradiation.\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"color:#212529\"\u003eOGG1-overexpressing AS52 cells (OGG1+): Fpg-sensitive sites reduced to 71% within half an hour and down to background levels at 4h.Wild type AS52 cells: at 4h, 70% of the Fpg-sensitive sites remained, indicating accumulation of oxidative lesions.\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"color:#212529\"\u003eMutations in the\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003cem\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"color:#212529\"\u003e\u003cem\u003eGpt\u003c/em\u003e\u003c/span\u003e\u003c/span\u003e\u003c/em\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"color:#212529\"\u003e\u0026nbsp;gene was quantified in both wild type and OGG1+ cells by sequencing after 13-15 days following 400 kJ/m\u003c/span\u003e\u003c/span\u003e\u003csup\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"color:#212529\"\u003e2\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/sup\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"color:#212529\"\u003eUVA irradiation\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"color:#212529\"\u003e.G:C\u0026rarr;T:A mutations in UVA-irradiated OGG1+ cells were completely eliminated (thus, repair was sufficient when repair overexpressed).G:C\u0026rarr;T:A mutation frequency in wild type cells increased from 1.8 mutants/million cells to 3.8 mutants/million cells following irradiation \u0026ndash; indicating incorrect repair or lack of repair of accumulated 8-oxo-dG.\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\r\n\t\u003cli style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eThere is evidence from knock-out/knock-down studies indicating there is a strong link between DNA repair adequacy and the frequency of mutations. Defects in proteins involved in DNA repair resulted in altered mutation frequencies in all of the instances studied when compared to wild-type cases. In cell lines deficient in LIG4 (Smith et al., 2003) and Ku80 (Feldmann et al., 2000), there were significant decline\u0026nbsp;in the frequency and accuracy of DNA repair; rescue experiments performed with these two cell lines further confirmed that inadequate DNA repair was the cause of the observed decreases in repair frequency and accuracy (Feldmann et al., 2000; Smith et al., 2003). There was more spontaneous DNA damage in Nibrin-deficient mouse cells than in wild-type controls, implying insufficient DNA repair.\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eIn vivo mutation frequencies were also observed to be higher in Nibrin-deficient mice than in wild-type mice using the corresponding Nibrin-deficient and wild-type mice (Wessendorf et al., 2014). Furthermore, depending on the XPC status of cancer patients, mutation densities in certain genomic areas were influenced differentially. In XPC-wild-type patients, mutation frequencies were higher at DHS promoters and 100 bp upstream of TSS than in cancer patients missing functional XPC (Perera et al., 2016). Finally,it was found that\u0026nbsp;radiation exposure caused four times more mutations in WKT1 cells with lower repair capacity than in TK6 cells with normal repair capacity in a research (Amundson and Chen, 1996).\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\r\n\t\u003cli style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eThere are findings that strongly link the different elements of DNA damage and repair events to the expression of miRNA.\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eZhang and coworkers examined genome-wide mature miRNA expression in Atm+/+ and Atm-/- littermate mouse embryonic fibroblasts to see how miRNAs are regulated in the DNA damage response (MEFs)(Zhang et al.,2011).\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eMEFs were given neocarzinostatin (NCS), a radiomimetic medication that causes DSBs (Ziv et al., 2006). Mouse miRNA microarray analysis was used to determine miRNA expression profile in each sample, which was done at several time points (0\u0026ndash;24 hr). As many as 71 distinct miRNAs were found to be considerably (2-fold) upregulated in the NCS-treated Atm+/+ MEFs, but not in the corresponding Atm-/- MEFs, implying that DNA damage stress causes broad-spectrum changes in miRNA expression.\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eAccording to Wan et al., regulatory RNA-binding proteins in the Drosha and Dicer complexes, such as DDX5 and KSRP, drive posttranscriptional processing of primary and precursor miRNAs after DNA damage. The findings show that nuclear export of pre-miRNAs is increased in an ATM-dependent manner after DNA damage. The ATM-activated AKT kinase phosphorylates Nup153, a main component of the nucleopore, resulting in enhanced interaction between Nup153 and Exportin-5 (XPO5) and increased nuclear export of pre-miRNAs. These findings demonstrate that DNA damage signalling is important for miRNA transport and maturation.\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eIn agreement with previous reports showing that ATM-activated p53 and KSRP promote miRNA expression (Suzuki et al., 2009; Zhang et al., 2011), the study found 61 p53-dependent miRNAs and 29 KSRP-dependent miRNAs among the ATM-induced miRNAs.\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\r\n\t\u003cli style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eIn Jiang et al\u0026#39;s study, the cellular function and molecular mechanism of miR2045p in hepatocellular cancer were investigated (HCC)(Jiang et al.,2016).\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eShen et al showed that downregulation of miR-199b is associated with distant metastasis in colorectal cancer via activation of SIRT1 and inhibition of CREB/KISS1 signalling(Shen et al.,\u0026nbsp;2016).\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eA study by Tian et al found that MicroRNA-133b targets Sirt1 and suppresses hepatocellular carcinoma cell progression(Tian et al.,\u0026nbsp;2016).\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eIn liver cancer, Yan et al discovered that MicroRNA 486 5p acts as a tumour suppressor of proliferation and cancer stem-like cell characteristics by targeting Sirt1(Yan et al.,2019).\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eZhang et al reported that MicroRNA-22 functions as a tumor suppressor by targeting SIRT1 in renal cell carcinoma (Zhang et al., 2016).\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\r\n\t\u003cli style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eAccording to Lu et al, SIRT1 inhibited the growth of gastric cancer through inhibiting the activation of STAT3 and NF-B (Lu et al.,2014). The goal was to look at SIRT1\u0026#39;s regulatory effects on gastric cancer (GC) cells (AGS and MKN-45) as well as the links between SIRT1 and STAT3 and NF-B activation in GC cells. The SIRT1 activator (resveratrol RSV) was discovered to contribute to the repression of viability and increase of senescence, which was reversed by SIRT1 inhibitor (nicotinamide NA) and SIRT1 depletion using the CCK-8 and SA-\u0026beta;-gal\u0026nbsp;assays, respectively. SIRT1 activation (RSV supplement) reduced not only STAT3 activation, including STAT3 mRNA level, c-myc mRNA level, phosphorylated STAT3 (pSTAT3) proteins, and acetylizad STAT3 (acSTAT3) proteins, but also pNF-B p65 and acNF-B p65 suppression. The effects of RSV were reversed by NA.\u003c/span\u003e\u003c/span\u003e\u0026nbsp;\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eFurthermore, when STAT3 or NF-B were knocked down, neither RSV nor NA could affect cellular survival or senescence in MKN-45 cells. Overall, the outcomes of the study revealed that SIRT1 activation could cause GC in vitro to lose viability and senescence. Furthermore, our findings demonstrated that SIRT1 inhibited proliferation in GC cells and was related to deacetylation-mediated suppression of STAT3 and NF-B protein activation\u003c/span\u003e\u003cem\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cem\u003e.\u003c/em\u003e\u003c/span\u003e\u003c/em\u003e\u003c/span\u003e\u0026nbsp;\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eThe levels of SIRT1 protein expression in non-small-cell lung cancer (NSCLC) cell lines were examined in a study by Yeung et al.,2004. In comparison to immortalised epithelial human lung NL-20 cells, NSCLC cells exhibit significant quantities of SIRT1 protein, as reported by other researchers (Luo et al, 2001; Vaziri et al, 2001).\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003ePharmacological modulators of Sirtuin activity were employed to see if NF-kB transcription was regulated by Sirtuins (Landry et al, 2000; Bedalov et al, 2001; Howitz et al, 2003).\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eTransient luciferase reporter experiments revealed that cells pretreated with resveratrol had very minimal NF-kB transcription following the presence of TNFa. TNFa-induced NF-kB activity was boosted when cells were pretreated with the Sirtuin inhibitors nicotinamide or splitomicin. NF-kB transcription was also potentiated in cells treated with trichostatin A (TSA), an HDAC class I and class II inhibitor, as expected.\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\r\n\t\u003cli style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eIn specific subclasses of human breast cancer cells and tumour tissue specimens, an enhanced level of activated NF-kB is found, primarily in erbB2-overexpressing ER-negative breast cancer (Biswas et al 2000;2003).\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eSingh et al explored a variety of methods to inhibit NF-kB activation in ER-negative breast cancer cells and looked at the effects on cell proliferation, apoptosis, and tumour growth in xenografts(Singh et al.,2007).\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eIn a prospective cohort study, Sampepajung et al used immunohistochemistry (IHC) to examine NF-B expression and intrinsic subtypes of breast cancer tissue and found a significant correlation between negative ER and overexpression of NF-B (p 0.05), with overexpression of NF-B being higher in negative ER (77.3 percent) compared to positive ER (47.4 percent )( Sampepajung et al., 2021).\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eLaere et al suggested that activation of NF-kB in inflammatory breast cancer (IBC) is associated with loss of estrogen receptor (ER) expression, indicating potential crosstalk between NF-kB and ER(Laere et al.,2007).\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eDifferential Sensitivity of ER \u0026alpha;\u0026nbsp;and ER\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u0026beta;\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u0026nbsp;Cells to the NF-kB Inhibitor Go6976\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u0026nbsp;was tested.\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u0026nbsp;A differential sensitivity to Go6976 by ER \u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u0026alpha;\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u0026nbsp;and ER\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u0026beta;\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u0026nbsp;breast cancer cells was observed (Holloway et al.,2004). The ER\u0026nbsp;\u0026alpha;\u0026nbsp;cells were more sensitive and less viable after treatment with this NF-kB inhibitor. The IC50 (50% killing) by Go6976 was 1 mM for Era of MDA-MB435 and MDA-MB231 breast cancer cells, whereas it was greater than 10 mM for ERa of MCF-7 and T47D or the normal mammary epithelial H16N \u0026nbsp;cells. At 10 mM Go6976, about 80% of the ERa cells were killed, whereas only 15\u0026ndash;30% of ERa and normal H16N cells were sensitive to this compound. The relative resistance of the H16N normal human mammary cells indicates a possible high therapeutic index of Go6976 against ERa cancer cells.\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\r\n\t\u003cli style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eEndogenous ER silencing causes EMT in ER-positive breast cancer cells. ER-positive MCF-7 cells were infected with ER shRNA lentiviral particles and stable clones were selected with puromycin (optimal dose of 0.8 g/mL) to knock down ER gene expression (Zheng et al.,2014). When the number of cell passages was increased following infection, the expression of ER was gradually knocked down.\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eSaleh et al. hypothesise that loss of oestrogen receptor function, which causes endocrine resistance in breast cancer, also causes trans-differentiation from an epithelial to a mesenchymal phenotype, which causes enhanced aggressiveness and metastatic tendency(Saleh et al., 2011).\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\r\n\t\u003cli style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u0026nbsp;EMT is the most crucial step in initiating metastasis, including metastasis to lymph nodes, because tumour cell movement is a pre-requisite for the metastatic process (Da et al., 2017). Multiple signalling pathways cause cancer cells to lose their cell-to-cell connections and cellular polarity during EMT, increasing their motility and invasive ness (Huang et al., 2017). MMPs cause E-cadherin to be cleaved, which increases tumour cell motility and invasion (Pradella et al., 2017).\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eChen et al investigated the potential function of MDM2 in ovarian cancer SKOV3 cells\u0026#39; EMT and metastasis(Chen et al.,2015).\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12pt\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eTGFbeta and Twist induce EMT by upregulating the expression of EMT markers such Snail, Vimentin, N-cadherin, and ABC transporters like ABCA3, ABCC1, ABCC3, and ABCC10 (Saxena et al., 2011).In the treatment with about 0.3, 3, 30 mM of doxorubicin, human mammary epithelial cells (HMLE) stably expressing Twist, FOXC2 or Snail demonstrate increased cell viability compared to control HMLE, dose-dependently (\u003c/span\u003e\u003ca href=\"#_ENREF_77\" title=\"Saxena, 2011 #119\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eSaxena et al., 2011\u003c/span\u003e\u003c/a\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e).\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\r\n\u003c/ul\u003e\r\n","weight_of_evidence_summary":"\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003ca href=\"https://aopwiki.org/relationships/2608\"\u003e\u003cspan style=\"color:#000000\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cstrong\u003eIncreased, DNA damage and mutation leads to Inadequate DNA repair\u003c/strong\u003e\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/a\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"color:#212529\"\u003eDNA base excision repair (BER\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"color:#212529\"\u003e)\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"color:#212529\"\u003e\u0026nbsp;and, to a lesser extent,\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"color:#212529\"\u003e\u0026nbsp;nucleotide excision repair\u003c/span\u003e\u003c/span\u003e\u0026nbsp;\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"color:#212529\"\u003e(\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"color:#212529\"\u003eNER\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"color:#212529\"\u003e) \u0026nbsp;are used to repair oxidative DNA damage. Previous research has found thresholded dose-response curves in oxidative DNA damage and attributed these findings to a lack of repair capability at the curve\u0026#39;s inflection point (Gagne et al., 2012; Seager et al., 2012). Following chemical exposures, in vivo, a rise and buildup of oxidative DNA lesions was seen despite the activation of BER, suggesting poor repair of oxidative DNA lesions beyond a certain level(Ma et al., 2008).\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eEmpirical Evidence (include consideration of temporal concordance ) has been documented in several studies as follows;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\u003cp style=\"text-align:justify\"\u003e\u0026nbsp;\u003c/p\u003e\r\n\r\n\u003ctable class=\"Table\" style=\"border-bottom:1px solid windowtext; border-left:1px solid windowtext; border-right:1px solid windowtext; border-top:1px solid windowtext; font-family:\u0026quot;Times New Roman\u0026quot;; font-size:13px; margin-left:3px\"\u003e\r\n\t\u003ctbody\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eCompound class\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eSpecies\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:88px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eStudy type\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:64px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eDose\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:148px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eKER findings\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:129px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eReference\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"color:#212529\"\u003eN,N-dimethylformamide\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eHomosapiens hepatocyte cell line\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:88px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eIn vitro\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eExperimental\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:64px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003emM\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:148px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eIncreased DNA damage leads to decreased DNA cross link repair mechanisms\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:129px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eWang et al.,2016\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eUV radiation\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eCricetulus griseus(Chinese hamster)\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:88px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e-do-\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:64px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003ekJ/m2\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:148px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e-do-\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:129px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eDahle et al.,2008\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eX-rays\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eHuman leukemia cell line\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:88px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e-do-\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:64px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eGy/min\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:148px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e-do-\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:129px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eLi et al.,2013\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eX rays\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eMice\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:88px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eIn vivo\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eExperimental\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:64px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eGy/min\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:148px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e-do-\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:129px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eLi et al.,2013\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eAniline\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eRat\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:88px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e-do-\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:64px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eKg/day\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:148px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e-do-\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:129px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eMa et al.,2008\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\u003c/tbody\u003e\r\n\u003c/table\u003e\r\n\r\n\u003cp style=\"text-align:justify\"\u003e\u0026nbsp;\u003c/p\u003e\r\n\r\n\u003cp style=\"text-align:justify\"\u003e\u0026nbsp;\u003c/p\u003e\r\n\r\n\u003cp style=\"text-align:justify\"\u003e\u0026nbsp;\u003c/p\u003e\r\n\r\n\u003ch1 style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:24pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cstrong\u003e\u003cstrong\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cstrong\u003eInadequate DNA repair leads to Increase, Mutations\u003c/strong\u003e\u003c/span\u003e\u003c/span\u003e\u003c/strong\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/h1\u003e\r\n\r\n\u003cp style=\"text-align:justify\"\u003e\u0026nbsp;\u003c/p\u003e\r\n\r\n\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eThere will be no increase in mutation frequency if DNA repair is capable of appropriately and efficiently repairing DNA lesions caused by a genotoxic stressor.\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eFor alkylated DNA, for example, efficient AGT removal will result in no increases in mutation frequency. However, once AGT reaches a certain dose, it becomes saturated and can no longer effectively remove alkyl adducts. Mutation occurs when O-alkyl adducts are replicated. The evidence that unrepaired O-alkylated DNA replication induces mutations in somatic cells is vast and has been evaluated. (Basu and Essigmann 1990; Shrivastav et al. 2010).\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eEmpirical Evidence (include consideration of temporal concordance ) has been documented in several studies as follows;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\u003cp style=\"text-align:justify\"\u003e\u0026nbsp;\u003c/p\u003e\r\n\r\n\u003ctable class=\"Table\" style=\"border-bottom:1px solid windowtext; border-left:1px solid windowtext; border-right:1px solid windowtext; border-top:1px solid windowtext; font-family:\u0026quot;Times New Roman\u0026quot;; font-size:13px; margin-left:4px\"\u003e\r\n\t\u003ctbody\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eCompound class\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eSpecies\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:88px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eStudy type\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:64px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eDose\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:148px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eKER findings\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:129px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eReference\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eUV radiation\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eChinese hamster\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:88px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eIn vitro\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:64px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003ekJ/m2\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:148px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003einadequate DNA repair leads to increased mutations\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:129px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eDahle et al.,2008\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u0026nbsp;\u003c/p\u003e\r\n\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u0026nbsp;\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eMice \u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:88px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eIn vivo\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:64px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u0026nbsp;\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:148px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e-do-\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:129px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eKlungland et al., 1999\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eX ray\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003ehuman\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:88px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eIn vitro\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:64px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eGy\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:148px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e-do-(dose-incidence)\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:129px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eMcmohan et al., 2016\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\u003c/tbody\u003e\r\n\u003c/table\u003e\r\n\r\n\u003cp style=\"text-align:justify\"\u003e\u0026nbsp;\u003c/p\u003e\r\n\r\n\u003ch1 style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:24pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cstrong\u003e\u003cstrong\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cstrong\u003eIncrease, Mutations leads to Increase,miRNA levels\u003c/strong\u003e\u003c/span\u003e\u003c/span\u003e\u003c/strong\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/h1\u003e\r\n\r\n\u003cp style=\"text-align:justify\"\u003e\u0026nbsp;\u003c/p\u003e\r\n\r\n\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eEvidences suggest that\u0026nbsp;transcription pathway for miRNAs is regulated in the DNA damage response\u0026nbsp;(DDR).Inadequate repair and mutations increase miRNA expression.\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eDNA damage-responsive transcription factors, such as NF-\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003ek\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eB, E2F, and Myc, are also involved in miRNA \u0026nbsp;transcription regulation.\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eThe p53 protein also functions as a transcriptional repressor by binding to miRNA promoters and preventing the recruitment of transcriptional activators.The empirical and dose response evidence for increased mutations inducing miRNA expression has been documented as follows;\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\u003ctable class=\"Table\" style=\"border-bottom:1px solid windowtext; border-left:1px solid windowtext; border-right:1px solid windowtext; border-top:1px solid windowtext; font-family:\u0026quot;Times New Roman\u0026quot;; font-size:13px; margin-left:4px\"\u003e\r\n\t\u003ctbody\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eCompound class\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eSpecies\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:80px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eStudy type\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:59px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eDose\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:134px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eKER findings\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:118px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eReference\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eNeocarzinostatin\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eMouse\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eFibroblast \u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:80px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eIn vitro\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:59px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eNg/ml\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:134px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eIncreased mutation leads to increased microRNA expression \u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u0026nbsp;\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u0026nbsp;\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:118px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eZiv et al.,2006\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eNeocarzinostatin\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eMouse\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eFibroblast\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:80px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eIn vitro\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:59px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eNg/ml\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:134px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e-do-\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:118px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eZhang et al.,2011\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eCisplatin and IR\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eHuman mammary epithelial cells\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:80px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eIn vitro\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:59px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003emM and Gy\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:134px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e-do-\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:118px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eJaarsveld et al., 2014\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\u003c/tbody\u003e\r\n\u003c/table\u003e\r\n\r\n\u003cp style=\"text-align:justify\"\u003e\u0026nbsp;\u003c/p\u003e\r\n\r\n\u003ch1 style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:24pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cstrong\u003e\u003cstrong\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cstrong\u003eIncrease,miRNA levels leads to Decrease,SIRT1(sirtuin 1) leves\u003c/strong\u003e\u003c/span\u003e\u003c/span\u003e\u003c/strong\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/h1\u003e\r\n\r\n\u003cp style=\"text-align:justify\"\u003e\u0026nbsp;\u003c/p\u003e\r\n\r\n\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eThere are several pathways which suggest suppression of SIRT1 \u0026nbsp;expression when miRNA is elevated.SIRT1 was downregulated at the mRNA and protein levels when miR-138 expression was increased. MiR-138 binds to the SIRT1 gene\u0026#39;s 3\u0026prime;UTR unique complimentary site and inhibits SIRT1 expression directly, preventing HCC proliferation, migration, and invasion (Luo \u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eet al.,2017).When compared to the normal hepatic cell line L02, SIRT1 is overexpressed, while miR-138 levels are lowered in HepG2, SMMC7721, Bel7404, and HCCM3 .\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eThe evidence for this fact has been listed as follows;\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\u003ctable class=\"Table\" style=\"border-bottom:1px solid windowtext; border-left:1px solid windowtext; border-right:1px solid windowtext; border-top:1px solid windowtext; font-family:\u0026quot;Times New Roman\u0026quot;; font-size:13px; margin-left:4px\"\u003e\r\n\t\u003ctbody\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eCompound class\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eSpecies\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:88px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eStudy type\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:148px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eKER findings\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:129px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eReference\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u0026nbsp;\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eHuman HCC Cell lines\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:88px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eIn vitro\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:148px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eIncreased miRNA leads to Reduced SIRT1\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:129px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eJiang et al.,2016;\u0026nbsp;Luo \u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eet al\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e.,2017; Tian \u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eet al.,\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u0026nbsp;2016; Yan \u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eet al.,2019; Bae et al.,2014;Zhou et al.,2017\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u0026nbsp;\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eHuman CRC cell lines\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:88px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eIn vitro\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:148px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e-do-\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:129px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eShen et al.,\u0026nbsp;2016;Lian et al.,2018\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u0026nbsp;\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eHuman RCC Cell lines\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:88px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eIn vitro\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:148px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e-do-\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:129px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eZhang et al., 2016;Fu et al.,2018\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eAstragalus Polysachcharide\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eProstate cancer cell lines\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:88px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eIn vitro\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:148px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e-do-\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:129px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eGuo et al.,2020;Yang et al.,2014\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u0026nbsp;\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eLung cancer cell lines\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:88px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eIn vitro\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:148px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e-do-\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:129px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eGuan et al.,2017\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\u003c/tbody\u003e\r\n\u003c/table\u003e\r\n\r\n\u003cp style=\"text-align:justify\"\u003e\u0026nbsp;\u003c/p\u003e\r\n\r\n\u003ch1 style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:24pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cstrong\u003e\u003cstrong\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cstrong\u003eDecrease,SIRT1(sirtuin 1) leves leads to Increase activation, Nuclear factor kappa B (NF-kB)\u003c/strong\u003e\u003c/span\u003e\u003c/span\u003e\u003c/strong\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/h1\u003e\r\n\r\n\u003cp style=\"text-align:justify\"\u003e\u0026nbsp;\u003c/p\u003e\r\n\r\n\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eSIRT1 suppresses NF-B signalling either directly by deacetylating the RelA/p65 subunit or indirectly by triggering repressive transcriptional complexes, which frequently involve heterochromatin formation at NF-B promoter regions. SIRT1 expression and signalling are both inhibited by NF-B.\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eZhang et al. \u0026nbsp;found that overexpressing RelA/p65 protein increased SIRT1 expression at both the transcriptional and protein levels (36 h treatment), whereas knocking down RelA/p65 expression decreased TNF-induced SIRT1 expression (8 h treatment)(Zhang et al.,2010). They also discovered that the RelA/p65 protein may bind to the SIRT1 promoter\u0026#39;s NF-B motifs. These findings suggest that NF-B may promote SIRT1 expression. Given that SIRT1 induction appeared to occur much later than NF-B activation, it appears that this action could represent a feedback response limiting inflammation and eventually generating endotoxin tolerance.\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eEvidences supporting this key event is as follows;\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\u003ctable class=\"Table\" style=\"border-bottom:1px solid windowtext; border-left:1px solid windowtext; border-right:1px solid windowtext; border-top:1px solid windowtext; font-family:\u0026quot;Times New Roman\u0026quot;; font-size:13px; margin-left:4px\"\u003e\r\n\t\u003ctbody\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eCompound class\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eSpecies\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:87px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eStudy type\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:145px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eKER findings\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:127px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eReference\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cem\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cem\u003enicotinamide\u003c/em\u003e\u003c/span\u003e\u003c/em\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eHuman gastric cancer cell lines\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:87px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eIn vitro\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:145px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eDecreased, SIRT1 leads to increased NF kB activity \u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:127px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cem\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cem\u003eLu \u003c/em\u003e\u003c/span\u003e\u003c/em\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eet al.,2014\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003enicotinamide or splitomicin\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003enon-small-cell lung cancer (NSCLC) cell lines\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:87px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eIn vitro\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:145px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eDecreased, SIRT1 leads to increased NF kB activity \u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:127px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eYeung et al.,2004;\u0026nbsp;Luo et al, 2001; Vaziri et al, 2001\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\u003c/tbody\u003e\r\n\u003c/table\u003e\r\n\r\n\u003cp style=\"text-align:justify\"\u003e\u0026nbsp;\u003c/p\u003e\r\n\r\n\u003cp style=\"text-align:justify\"\u003e\u0026nbsp;\u003c/p\u003e\r\n\r\n\u003ch1 style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:24pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cstrong\u003e\u003cstrong\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cstrong\u003eIncrease activation, Nuclear factor kappa B (NF-kB) leads to Antagonism, Estrogen receptor\u003c/strong\u003e\u003c/span\u003e\u003c/span\u003e\u003c/strong\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/h1\u003e\r\n\r\n\u003cp style=\"text-align:justify\"\u003e\u0026nbsp;\u003c/p\u003e\r\n\r\n\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eNF-kB activation in breast cancer has been extensively documented in oestrogen receptor negative (ER) breast tumours and ER breast cancer cell lines, implying a significant inhibitory interaction between both signalling pathways (Biswas et al, 2000, 2001, 2004; Zhou et al, 2005). A rise in both NF-kB DNA-binding activity (Nakshatri et al, 1997) and expression of NF-kB target genes such IL8 coincides with a transition from oestrogen dependence to oestrogen independence in breast cancer, indicating inhibitory cross-talk. The fact that some breast tumours that are resistant to the tumoricidal action of anti-estrogens become sensitised to apoptosis and show a drop in NF-kB activity after treatment with oestrogen supports the inverse relationship between ER and NF-kB activity. \u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e-This shows that oestrogen\u0026#39;s proapoptotic actions in these tumours are mediated via NF-kB suppression.\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\u003cp style=\"text-align:justify\"\u003e\u0026nbsp;\u003c/p\u003e\r\n\r\n\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eBoth in vivo and in vitro studies support the finding;\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\u003ctable class=\"Table\" style=\"border-bottom:1px solid windowtext; border-left:1px solid windowtext; border-right:1px solid windowtext; border-top:1px solid windowtext; font-family:\u0026quot;Times New Roman\u0026quot;; font-size:13px; margin-left:4px\"\u003e\r\n\t\u003ctbody\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eCompound class\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eSpecies\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:88px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eStudy type\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:64px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eDose\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:148px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eKER findings\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:129px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eReference\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eBortezomib\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eBreast cancer cell lines\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:88px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eIn vitro\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:64px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u0026nbsp;\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:148px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eIncreased activity of NF kB, \u0026nbsp;leads to Reduced Estrogen receptor expression\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:129px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eSingh et al.,2017;\u0026nbsp;Holloway et l.,2004\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u0026nbsp;\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u0026nbsp;\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eHuman Breast tissue\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:88px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eIn vivo\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:64px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u0026nbsp;\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:148px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e-do-\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:129px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eBiswas et al 2000;2003\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u0026nbsp;\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eHuman Breast tissue\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:88px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eIn vivo\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:64px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u0026nbsp;\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:148px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e-do-\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:center; width:129px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eSampepajung et al., 2021; Laere et al.,2007; Indra et al.,2021;\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\u003c/tbody\u003e\r\n\u003c/table\u003e\r\n\r\n\u003cp style=\"text-align:justify\"\u003e\u0026nbsp;\u003c/p\u003e\r\n\r\n\u003ch1 style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:24pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cstrong\u003e\u003cstrong\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cstrong\u003eAntagonism, Estrogen receptor leads to EMT\u003c/strong\u003e\u003c/span\u003e\u003c/span\u003e\u003c/strong\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/h1\u003e\r\n\r\n\u003cp style=\"text-align:justify\"\u003e\u0026nbsp;\u003c/p\u003e\r\n\r\n\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eE2/ERa signalling, in part through transcriptional activation of luminal/epithelial-related transcription factors, promotes the development of mammary epithelia along a luminal/epithelial lineage. GATA3 and ERa both promote each other (Eeckhoute et al.,2007)\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e. In normal breast epithelia, GATA3 is needed for luminal differentiation(Kouros-Mehr \u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eet al.,2008)\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u0026nbsp;and GATA3 and ERa control many of the same genes (Wilson \u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eet al.,2008)\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e. \u0026nbsp;In mice, forcing GATA3 expression in mesenchymal breast cancer cells produces mesenchymal\u0026ndash;epithelial transition (MET), a reversible mechanism analogous to EMT, and prevents tumour metastasis (Yan \u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eet al.,2010)\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e. Another ERa-interacting transcription factor, FOXA1, is essential for luminal lineage in mammary epithelia and stimulates ductal development in mice (Bernardo \u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eet al.,2010)\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e. FOXA1 enhances ERa gene expression by increasing the accessibility of estrogen-response regions for ERa binding (Nakshatri \u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eet al.,\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u0026nbsp;2009). In breast cancer cells, on the other hand, E2 appears to increase FOXA1 expression. Importantly, ERa, FOXA1, and GATA3 are all positive breast cancer prognostic factors(Nakshatri \u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eet al.,2009).\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\u003cp style=\"text-align:justify\"\u003e\u0026nbsp;\u003c/p\u003e\r\n\r\n\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eYe et al. \u0026nbsp;investigated the impact of ERa overexpression in ERa-negative breast cancer cell lines (MDA-MB-468, MDA-MB-231) or ERa knockdown in ERa-positive cell lines (MCF-7, T47D) on Slug and Snail expression and phenotypes in ERa-positive cell lines (MCF-7, T47D)(Ye et al., 2010). Slug is repressed, E-cadherin is increased, and cells develop as adherent colonies with less invasiveness when ERa is forced to get\u0026nbsp;expressed. ERa knockdown, on the other hand, causes an increase in Slug expression, a decrease in E-cadherin, and spindle-shaped invasive cells.\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\u003cp style=\"text-align:justify\"\u003e\u0026nbsp;\u003c/p\u003e\r\n\r\n\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eWik et al used integrated molecular profiling to examine Endometrial cancer samples from a primary investigation cohort and three independent validation cohorts (Wik et al.,2013). Patient survival was closely linked to ER-a immunohistochemical staining and receptor gene (ESR1) mRNA expression. In the study cohort, ER-a negative was related with activation of genes implicated in Wnt, Sonic Hedgehog, and TGF-b signalling, indicating epithelial\u0026ndash;mesenchymal transition (EMT)\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\u003cp style=\"text-align:justify\"\u003e\u0026nbsp;\u003c/p\u003e\r\n\r\n\u003ch1 style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:24pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cstrong\u003e\u003cstrong\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cstrong\u003eEMT leads to Metastasis, Breast Cancer\u003c/strong\u003e\u003c/span\u003e\u003c/span\u003e\u003c/strong\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/h1\u003e\r\n\r\n\u003cp style=\"text-align:justify\"\u003e\u0026nbsp;\u003c/p\u003e\r\n\r\n\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eThe \u0026ldquo;epithelial\u0026ndash;mesenchymal transition\u0026rdquo; (EMT), a key developmental regulatory program, has been reported to play critical and intricate roles in promoting tumor invasion and metastasis in epithelium-derived carcinomas.\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u0026nbsp;\u0026quot;EMT is marked by a decrease in E-cadherin expression, increase in vimentin, fibronectin, and N-cadherin expression, and translocation of beta-catenin into the nucleus\u0026#39;\u0026#39;(Irani et al., 2018). EMT is a master mechanism in cancer cells that allows them to lose their epithelial characteristics and gain mesenchymal-like qualities. EMT is the most crucial step in initiating metastasis, including metastasis to lymph nodes, because tumour cell movement is a pre-requisite for the metastatic process (Da et al., 2017). Multiple signalling pathways cause cancer cells to lose their cell-to-cell connections and cellular polarity during EMT, increasing their motility and invasive ness (Huang et al., 2017). MMPs cause E-cadherin to be cleaved, which increases tumour cell motility and invasion (Pradella et al., 2017).\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\u003cp style=\"text-align:justify\"\u003e\u0026nbsp;\u003c/p\u003e\r\n\r\n\u003cp style=\"text-align:justify\"\u003e\u0026nbsp;\u003c/p\u003e\r\n\r\n\u003cp style=\"text-align:justify\"\u003e\u0026nbsp;\u003c/p\u003e\r\n","quantitative_considerations":"\u003cp\u003e\u0026nbsp;\u003c/p\u003e\r\n\r\n\u003cp\u003eThe techniques used for quantifying KE\u0026#39;s were reliable with repeatability and reproducibility. Assays were fit for the purpose.\u003c/p\u003e\r\n\r\n\u003ctable cellspacing=\"0\" class=\"MsoTableGrid\" style=\"border-collapse:collapse; border:none; font-family:\u0026quot;Times New Roman\u0026quot;; font-size:13px; text-align:justify; width:976px\"\u003e\r\n\t\u003ctbody\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:2px solid black; vertical-align:top; width:73px\"\u003e\r\n\t\t\t\u003cp\u003e\u0026nbsp;\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:2px solid black; vertical-align:top; width:139px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003eMIE 1669\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:2px solid black; vertical-align:top; width:128px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003eKE 155\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:2px solid black; vertical-align:top; width:120px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003eKE 185\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:2px solid black; vertical-align:top; width:126px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003eKE1980\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:2px solid black; vertical-align:top; width:131px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003eKE1981\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:2px solid black; vertical-align:top; width:128px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003eKE 1172\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:2px solid black; vertical-align:top; width:135px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003eKE 112\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:2px solid black; vertical-align:top; width:106px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003eKE1457\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:2px solid black; vertical-align:top; width:130px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003eAO1982\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:73px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003eHuman\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:139px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003ePCR-RFLP \u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003e8-OHdG \u0026ndash; ELISA \u0026amp; MDA \u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003e(\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#212121\"\u003eChen CH et al 2011\u003c/span\u003e\u003c/span\u003e)\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u0026nbsp;\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:128px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003e-\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:120px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003eAcetaldehyde assay,\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003eExtract preparation and Western blotting,\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003eN\u003csup\u003e2\u003c/sup\u003e- Ethyl dGuo quantitation\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003eAbraham J et al 2011\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:126px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003e-\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:131px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003e-\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:128px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003eqRT-PCR,immunohistochemistry (\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#212121\"\u003eMcGlynn LM et al 2014\u003c/span\u003e\u003c/span\u003e)\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp\u003e\u0026nbsp;\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:135px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003eqRT-PCR, immunohistochemistry (Sampepajung E et al 2021, Van Laere SJ et al 2007,)\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:106px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003eIHC,micro array,qPCR, SNP array(\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#212121\"\u003eWik E et al 2013\u003c/span\u003e\u003c/span\u003e)\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:130px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003eLiang et al., 2013;Liu et al., 2016;Zhang et al.,2015; Chen et al., 2015;Yue et al.,2019;Wang et al., \u0026nbsp;2018;Yu et al.,2017\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:73px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003eHuman Tissues\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:139px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003e-\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:128px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003e-\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:120px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003e-\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:126px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003e-\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:131px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003eqRT-PCR,Western blotting,Luciferase reporter assay H2,H4,H7,H8,H9\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003eMicro-array (Shen ZL et al 2016)\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:128px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003e-\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:135px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003e-\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:106px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003e-\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:130px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003e-\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:73px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003eHuman Cell lines\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:139px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003eRT- PCR, Western Blot \u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003eMAPK assay, Immunoprecipitation,\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003eWestern immunoblotting \u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003eThymidine uptake \u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003eECL-SDS PAGE, \u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003eRIA \u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003eAdduct removal measurements,\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003eDNA isolation, \u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003eTLC, \u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003eLCMS \u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003eAcetaldehyde estimation, \u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003eDNA adducts \u0026ndash; LC-ESI-MS/ MS-SRM, Western blotting \u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003eWestern blotting, enzymatic assay, \u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003eLC-ESI-MS/ MS-SRM \u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003eDNA oxidative damage by ELISA, Immunofluorescence, cell culture, \u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003e8-OHdG \u0026ndash; ELISA \u0026amp; Ph2A\u003cspan style=\"background-color:#ffffff\"\u003e\u0026lambda;\u0026ndash;fociformation assays, \u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003eP53 luciferase assays, \u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003eqPCR, \u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003eWestern Blotting\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e(\u003c/span\u003eElise A. Triano\u0026nbsp;et al 2003,\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003eEtique.Nicolas etiqu\u0026nbsp;et al 2004,\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003eIzevbigie EB\u003c/span\u003e\u0026nbsp;et al 2002,\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003ePrzylipiak A\u003c/span\u003e\u0026nbsp;et al 1996,\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003eSingletary KW et al 2001,\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003eSingletary KW et al 2004,\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003eAbraham J et al 2011,\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003eZhao M et al 2017,\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003eJessy \u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#212121\"\u003eAbraham J et al 2011\u003c/span\u003e)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:128px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003e-\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:120px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003e-\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:126px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003eWestern blotting,clonal survival assay,FACs(van Jaarsveld MT et al 2014)\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:131px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003eMicro-array, qRT-PCR,Western blotting,Luciferase reporter assay\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003e(Guo S et al 2020,\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003eBae HJ et al 2014,\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003eZhou J et al 2017,\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003eFu H et al 2018,\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003eLian B et al 2018\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003eGuan Y et al 2017\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003eYang X et al 2014)\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp\u003e\u0026nbsp;\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:128px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003eqRT-PCR,,Luciferase reporter assay \u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003eCell based HDAC assay(\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#212121\"\u003eYeung F et al 2004\u003c/span\u003e\u003c/span\u003e)\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:135px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003eqPCR, western blotting, immunoprecipitation, immunofluorescent microscopy, Luciferase reporter assay \u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003eEMSA,\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003eIHC,Cell viability assay (Singh S et al 2007, Holloway JN \u0026nbsp;et al 2004,\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003eBiswas DK et al 2000,\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003eSong RX et al 2005,\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003eScherbakov AM et al 2005,\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003eScherbakov AM et al 2009)\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:106px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003eqRT-PCR,cell viability assay,\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003eWestern blotting,EdU incorporation assay(\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#212121\"\u003eBouris P\u003c/span\u003e\u003c/span\u003e\u0026nbsp;et al 2015, \u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#212121\"\u003eLiu Y\u003c/span\u003e\u003c/span\u003e\u0026nbsp;et al 2015,\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#212121\"\u003eAl Saleh S\u003c/span\u003e\u003c/span\u003e\u0026nbsp;et al 2011,\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#212121\"\u003eZeng Q\u003c/span\u003e\u003c/span\u003e\u0026nbsp;et al 2014,\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#212121\"\u003eYe Y\u003c/span\u003e\u003c/span\u003e\u0026nbsp;et al 2010,\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003eLin, HY\u003c/span\u003e\u003c/span\u003e\u0026nbsp;et al 2018)\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:130px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003eqRT-PCR,,Luciferase reporter assay ,immunoblotting,immunoprecipitation,cell invasion assay,cell migration assay, bioluminesence imaging,wound healing assay,Wound scratch \u0026amp; Transwell assay, Microarray,Immunofluorescence, Immunohistochemistry,\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003eGujral et al.,2014;Cui et al.,2013;Shiota et al.,2012;Gao et al.,2018;Chen et al.,2017;Liu et al.,2020;Casas et al.,2011;Jackstadt et al.,2013;Kong et al.,2016;Zhang et al.,2014;Huang et al.,2014\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp\u003e\u0026nbsp;\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:73px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003eRat\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:139px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003eFree radical assay\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003eGC-MS-SIM \u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003e\u0026nbsp;(Hackney JF\u0026nbsp;et al 1992,\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003eMcDermott EW\u0026nbsp;et al 1992)\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:128px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003eQuantification of ATase activity \u0026ndash; BSA method\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003eAPNG assay,\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003eOXOG glycosylase activity assay,\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003eWestern immunoblotting,\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003eImmunohistochemical detection of ATase. (Kotova N et al, 2013)\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:120px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003e-\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:126px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003eFree radicCyQuant cell Proliferation assay (Abdelfattah, N. et al 2018)\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:131px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003e-\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:128px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003e-\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:135px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003e-\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:106px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003e-\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:130px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003e-\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:73px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003eRat Cell lines\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:139px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003e-\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:128px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003eFlow cytometric micronucleus assay,\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003eCell cycle analysis,\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003eReplication fork elongation assay,\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003eCytotoxicity assay,\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003eRecombination assay, (\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#2a2a2a\"\u003ePanida Navasumrit et al, 2001\u003c/span\u003e\u003c/span\u003e)\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:120px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003e-\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:126px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003e-\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:131px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003e-\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:128px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003e-\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:135px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003e-\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:106px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003e-\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:130px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003e-\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:73px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003eMice\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:139px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003eComet assay, \u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003eROS generation assay. \u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003e(Lei \u0026nbsp;Guo et al 2008)\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:128px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003eFISH karyotyping,\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003eInvivo point mutation assay,\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003eWhole genome sequencing of HSC clones. (\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#212121\"\u003eGaraycoechea JI et al, 2012\u003c/span\u003e\u003c/span\u003e)\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:120px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003eIn vivo point mutation assay\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003eGaraycoechea JI et al, 2018\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:126px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003eFree radicCyQuant cell Proliferation assay (Abdelfattah, N. et al 2018)\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003eRNA sequence analysis,Immuno staining,immunoblotting,Flowcytometry,COMET assay,qRT PCR(Liu Z et al 2017)\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003eMicroarray (Zhang X et al 2011)\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003eqRT PCR,RIP assay,Immunogold EM(Wan G et al 2013)\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:131px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003eqRT-PCR,Western blotting,Luciferase reporter assay,ELISA,cell culture\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003eBai XZ et al 2018\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:128px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003eqRT-PCR,Southern and northern blotting, reporter gene \u0026nbsp;assay(Paul T et al 2008)\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:135px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003eEMSA,Autoradiography,Immunofluorescent microscopy, Westernblotting (Biswas DK et al 2001)\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:106px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003e-\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:130px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003eChen et al.,2017; Gumireddy et al.,2009; Yu et al., 2016; Sarkar et al.,2015\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp\u003e\u0026nbsp;\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:73px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003eCanine\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:139px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003e-\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:128px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003e-\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:120px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003e-\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:126px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003emicro array(Bulkowska M et al 2017)\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:131px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003e-\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:128px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003e-\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:135px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003e-\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:106px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003e-\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:130px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003e-\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:73px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003eYeast\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:139px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003e-\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:128px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003e-\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:120px\"\u003e\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003eFluctuation assay\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003eVoordeckers K et al, 2020\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp\u003e\u0026nbsp;\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:126px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003e-\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:131px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003e-\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:128px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003e-\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:135px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003e-\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:106px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003e-\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:130px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12px\"\u003e-\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\u003c/tbody\u003e\r\n\u003c/table\u003e\r\n","optional_considerations":"\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:11pt\"\u003e\u003cspan style=\"font-size:12.0pt\"\u003eIntended uses of this AOP:\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\u003cul\u003e\r\n\t\u003cli\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:11pt\"\u003e\u003cspan style=\"font-size:12.0pt\"\u003eHelpful for risk assessors, in assessing the risk of alcohol on metastatic breast cancer\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\r\n\t\u003cli\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:11pt\"\u003e\u003cspan style=\"font-size:12.0pt\"\u003eIf the causal relationship is established between key events, it may be useful drug targets\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\r\n\t\u003cli\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:11pt\"\u003e\u003cspan style=\"font-size:12.0pt\"\u003eAn alternative model to animal model based test methods\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\r\n\u003c/ul\u003e\r\n","references":"\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e44.Non-Technical Summary Archived 24 July 2006 at the Wayback Machine. 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Oncology letters, 14(6), 6950-6954.\u003c/span\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003eZhou, Y., Eppenberger-Castori, S., Eppenberger, U., \u0026amp; Benz, C. C. (2005). The NFkB pathway and endocrine-resistant breast cancer. Endocrine Related Cancer, 12(1), S37.\u003c/span\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003eZovoilis, A., Agbemenyah, H. Y., Agis‐Balboa, R. C., Stilling, R. M., Edbauer, D., Rao, P., ... \u0026amp; Fischer, A. (2011). microRNA‐34c is a novel target to treat dementias. The EMBO journal, 30(20), 4299-4308.\u003c/span\u003e\u003c/p\u003e\r\n","overall_assessment":"\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-size:14px\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"color:#212529\"\u003e\u003cstrong\u003eIncreased DNA damage and mutations [Evidence: high]\u003c/strong\u003e:\u0026nbsp;\u003c/span\u003eDNA damage refers to a\u003cspan style=\"background-color:white\"\u003e\u003cspan style=\"color:#333333\"\u003eny modification in the physical and/or chemical structure of DNA resulting in an altered DNA molecule that is different from the original DNA molecule with regard to its physical, chemical, and/or structural properties\u0026quot;.\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"color:#333333\"\u003eExternal factors to the cell such as environmental or potentially aggressive factors produced by the normal cell metabolism can damage the DNA. The effects caused by the action of endogenous factors may be more serious and/or more extensive than the effect of most of the exogenous DNA damaging factors.\u0026nbsp;\u003c/span\u003eEvidence suggested that prolonged alcohol intake is positively associated with an increased risk of cancer.\u0026nbsp; It can cause changes in the sequence of genomic DNA, which may act as a tumor promoter as well. Alcohol consumption can result in the generation of DNA-damaging molecules such as reactive oxygen species (ROS), lipid peroxidation products, and acetaldehyde. Strand breaks and oxidative base damage in DNA can be produced by hydroxyl radicals which are both mutagenic and cytotoxic.\u0026nbsp;Alcohol is a known inducer of microsomal oxidizing system, which includes a specific ethanol-inducible form of cytochrome \u003cstrong\u003eP450, \u003c/strong\u003ereferred to as CYP2EL (Lieber C 1992). This effect on the enzyme system has been associated with liver pathology induced by alcohol (Morimoto M et al 1993, French S et al 1993, Nanji A et al 1994, Albano E et al 1996). Again the damaging effects of high levels of CYP2E1 may be mediated by the generation of ROS (Cederbaum 1989, Reinke L et al 1990, Ishii H et al 1989). ROS that is highly reactive, include the oxygen radicals superoxide anion and hydroxyl radicals and can react with lipids, proteins, and DNA and thereby damage them (Knecht K et al 1990).\u0026nbsp; It has been confirmed in vivo experiments that hydroxyethyl radical formation takes place after ethanol exposure (Albano E et al 1996, Moore D et al 1995, \u003cspan style=\"background-color:white\"\u003e\u003cspan style=\"color:#222222\"\u003eClot, P\u003c/span\u003e\u003c/span\u003e et al 1996, Thurman R 1973). Chronic exposure to ethanol also results in increased production of H\u003csub\u003e2\u003c/sub\u003e0\u003csub\u003e2\u003c/sub\u003e, (Kukieka E et al 1992, \u003cspan style=\"background-color:white\"\u003e\u003cspan style=\"color:#222222\"\u003eKukielka, E., \u0026amp; Cederbaum, A. I. 1994\u003c/span\u003e\u003c/span\u003e) which can react with metal ions (such as iron in the Fenton reaction); thus resulting in the production of the highly reactive hydroxyl radicals. DNA is very sensitive to the attack by the hydroxyl radical. A sensitive assay for hydroxyl radical formation from CYP2E1 uses DNA damage (strand breakage) as an endpoint (Breen AP, Murphy JA 1995). Apart from this, more than twenty\u003cstrong\u003e \u003c/strong\u003edifferent types of DNA base damage with diverse biological properties are produced by hydroxyl radical (Moriya M 1993).8-hydroxy-2\u0026#39;-deoxyguanosine, is one such DNA lesion brought about by oxidative stress.\u003cstrong\u003e\u0026nbsp; This is\u0026nbsp;\u003c/strong\u003emutagenic, due to the tendency of DNA polymerases to misincorporate deoxyadenosine residues opposite this oxidized base (Song B 1996).\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\u003cp style=\"text-align:justify\"\u003e\u0026nbsp;\u003c/p\u003e\r\n\r\n\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-size:14px\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cstrong\u003e\u003cspan style=\"color:#212529\"\u003eInadequate DNA cross-link repair mechanisms\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003cspan style=\"color:#212529\"\u003e\u003cstrong\u003e[Evidence:high]\u003c/strong\u003e:\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-size:14px\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003eAs a result of DNA damage, DNA repair activities change. A variety of genotoxic agents, such as N-nitrosodimethylamine, aflatoxin B1, and 2-acetylaminofluorene induce the protein, O6-Alkylguanine-DNA alkyltransferase (ATase), are\u0026nbsp;responsible for the repair of DNA alkylation damage in rats (O\u0026rsquo;Connor, 1989; Chinnasamy et al.,1996). Grombacher and Kaina (1996) reported an increased human ATase mRNA expression by alkylating agents like N-methyl-N\u0026prime;-nitro-N-nitrosoguanidine and methyl methanesulphonate and by ionizing radiation via the induction of the ATase promoter. ATase mRNA expression was increased in response to treatment with 2-acetylaminofluorene in rat liver (Potter et al., 1991; Chinnasamy et al., 1996). In another study, it was demonstrated that ATase gene induction is p53 gene-dependent: ATase activity was induced in mouse tissues following \u0026gamma;-irradiation in p53 wild-type mice, but not in p53 null animals (Rafferty et al., 1996).\u0026nbsp;Alkylating agents and X-rays also induce DNA glycosylase, alkylpurine-DNA-N-glycosylase (APNG) \u0026nbsp;(Lefebvre et al., 1993; Mitra and Kaina, 1993).\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\u003cp style=\"text-align:justify\"\u003e\u0026nbsp;\u003c/p\u003e\r\n\r\n\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-size:14px\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cstrong\u003e\u003cspan style=\"color:#212529\"\u003eIncreased mutations\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003cspan style=\"color:#212529\"\u003e\u003cstrong\u003e[Evidence: moderate]\u003c/strong\u003e:\u0026nbsp;\u003c/span\u003e\u003cspan style=\"background-color:white\"\u003e\u003cspan style=\"color:black\"\u003eInadequate repair causes damaged DNA to be retained and used as a template during DNA replication. Incorrect nucleotides may be inserted during the replication of damaged DNA, and these nucleotides become \u0026#39;fixed\u0026#39; in the cell after replication. The mutation propagates to more cells as a result of further replication.\u0026nbsp;Non-homologous end joining (NHEJ) is one of the repair methods employed in human somatic cells to repair DNA double-strand breaks (DSBs). (Petrini et al., 1997; Mao et al., 2008). \u003c/span\u003e\u003c/span\u003eHowever, this mechanism is prone to errors and may result in mutations during the DNA repair process. (Little, 2000). As it does not use a homologous template to repair the DSB, NHEJ is considered error-prone. Many proteins work together in the NHEJ pathway to bridge the DSB gap by overlapping single-strand termini that are typically less than 10 nucleotides long. (Anderson, 1993; Getts \u0026amp; Stamato, 1994; Rathmell \u0026amp; Chu, 1994). Errors are introduced during this process, which can result in mutations like insertions, deletions, inversions, or translocations.\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\u003cp style=\"text-align:justify\"\u003e\u0026nbsp;\u003c/p\u003e\r\n\r\n\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-size:14px\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cstrong\u003e\u003cspan style=\"color:#212529\"\u003eIncreased micro RNA expression\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003cspan style=\"color:#212529\"\u003e\u003cstrong\u003e[Evidence: moderate]\u003c/strong\u003e:\u0026nbsp;\u003c/span\u003eDNA damage-responsive transcription factors, such as NF-kB, E2F, and Myc, are also involved in miRNA transcription regulation. The p53 protein also functions as a transcriptional repressor by binding to miRNA promoters and preventing the recruitment of transcriptional activators.\u0026nbsp;For example, p53 prevents the TATA-binding protein from binding to the TAATA site in the promoter of the miR-17-92 cluster gene, suppressing transcription. Under hypoxic conditions, the miR-17-92 cluster is suppressed by a p53-dependent mechanism, making cells more susceptible to hypoxia-induced death (Yan et al.,2009).\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-size:14px\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cstrong\u003e\u003cspan style=\"color:#212529\"\u003eDecreased SIRT1 expression\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003cspan style=\"color:#212529\"\u003e\u003cstrong\u003e[Evidence: moderate]\u003c/strong\u003e:\u0026nbsp;\u003c/span\u003eThere are several signaling pathways that establish the role of increased miRNA expression in downregulating the SIRT 1 gene few of which are listed as follows; Butyrate has been demonstrated to cause apoptosis and reduce carcinogenesis in a variety of cancers (Tailor et al.,2014; Rahmani et al.,2002). Although butyrate has been shown to suppress SIRT1 gene expression in various cancers, this has yet to be proven in hepatocellular carcinoma (HCC) (Iglesias et al., 2007). In HCC, miR-22 was found to be downregulated, and its low levels aided carcinogenesis (Zhang et al.,2010). The Huh7 cells\u0026#39; in vitro proliferation was decreased by miR-22 expression, which activated apoptosis. In Huh7 cells, on the other hand, SIRT1 expression was high, which enhanced the expression of antioxidants such as superoxide dismutase (SOD), allowing cell growth to continue (Chen et al.,2012). Butyrate upregulated miR-22 in Huh7 cells, which binds directly to the 3\u0026prime;UTR region of SIRT1 and suppresses its expression.Notch3\u0026ndash;SIRT1\u0026ndash;LSD1\u0026ndash;SOX2 Signaling Pathway\u003cstrong\u003e\u0026nbsp;in\u0026nbsp;\u003c/strong\u003emetastasis (Wang et al.,2016; Wu et al .,2017).MiR-486 inhibits HCC invasion and tumorigenicity by directly targeting and suppressing SIRT1 expression. This reduced the tumorigenic and chemo-resistant features of LCSCs and inhibited HCC invasion and tumorigenicity (Yan et al.,2019).\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-size:14px\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cstrong\u003e\u003cspan style=\"color:#212529\"\u003eIncreased activity of NF kB\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003cspan style=\"color:#212529\"\u003e\u003cstrong\u003e[Evidence: moderate]\u003c/strong\u003e:\u0026nbsp;\u003c/span\u003eSIRT1 deacetylates\u0026nbsp; NFkB. In the context of NFkB, all of the evidence so far points to its signaling being inhibited after SIRT1 deacetylation (Morris, 2012). According to Yeung et al, SIRT1 can directly interact with and deacetylate the RelA/p65 component of the NF-B complex (Yeung et al.,2004). \u003cspan style=\"color:#202122\"\u003eNF-B can be activated by cytokines (TNF-, IL-1), growth factors (EGF), bacterial and viral products (lipopolysaccharide (LPS), dsRNA), UV and ionizing radiation, reactive oxygen species (ROS), DNA damage, and oncogenic stress from inside the cells. Almost all stimuli eventually activate a large cytoplasmic protein complex called the inhibitor of B (IB) kinase (IKK) complex via a so-called \u0026quot;canonical pathway.\u0026quot; The exact composition of this complex is unknown, however, it has three fundamental components: IKK1/IKK, IKK2/IKK, and NEMO/IKK. IB is phosphorylated by the activated IKK complex, which marks it for destruction by the -transducin repeat-containing protein (-TrCP)-dependent E3 ubiquitin ligase-mediated proteasomal degradation pathway (Liu et al., 2012;Li et al., 2002). As a result, unbound NF-B dimers can go from the cytoplasm to the nucleus, bind to DNA, and control gene transcription.\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-size:14px\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cstrong\u003eAntagonism of\u0026nbsp;\u003cspan style=\"color:#212529\"\u003eestrogen receptor\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003cspan style=\"color:#212529\"\u003e\u003cstrong\u003e[Evidence: moderate]\u003c/strong\u003e:\u0026nbsp;\u003c/span\u003eActivation NF-\u0026kappa;B in breast cancer leads to loss of Estrogen Receptor (ER) expression and Human Epidermal Growth Factor Receptor 2 (HER-2) overexpressed via epidermal growth factor receptor (EGFR) and Mitogen-Activated Protein Kinase (MAPK) pathway (Laere et al.,2007). Indeed, the binding of epidermal growth factor (EGF) to its receptor (EGFR) activates NF-B, which most likely contributes to this transcription factor\u0026#39;s increased activity in ER-negative breast cancer cells (Shostak et al.,2011). Because of the constitutive production of cytokines and growth factors, loss of ER function has been linked to constitutive NF-kB activity and hyperactive MAPK, resulting in aggressive, metastatic, hormone-resistant malignancies (Ali et al., 2002). Activation of the progesterone receptor can reduce DNA binding and transcriptional activity by inhibiting NF-B-driven gene expression (Kalkhoven et al., 1996). HER-2 stimulates NF-B via the conventional route, which includes IKK (Merkhofer et al., 2010).\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-size:14px\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cstrong\u003e\u003cspan style=\"color:#212529\"\u003eEpithelial-mesenchymal transition cell\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003cspan style=\"color:#212529\"\u003e\u003cstrong\u003e[Evidence: high]\u003c/strong\u003e:\u0026nbsp;\u003c/span\u003eEstrogen/ERa signaling maintains an epithelial phenotype and suppresses EMT.ERa signaling promotes proliferation and epithelial differentiation and opposes EMT. Various studies support this finding (Eeckhoute et al.,2007, Kouros-Mehr et al.,2008, Nakshatri et al., 2009, Taylor et al.,2010).\u0026nbsp;ER-a negative was related to activation of genes implicated in Wnt, Sonic Hedgehog, and TGF-b signaling, indicating epithelial-mesenchymal transition (EMT)(Wik et al.,2013).\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-size:14px\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cstrong\u003e\u003cspan style=\"color:#212529\"\u003eMetastatic breast cancer\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003cspan style=\"color:#212529\"\u003e\u003cstrong\u003e[Evidence: high]\u003c/strong\u003e:\u0026nbsp;\u003c/span\u003eThe \u0026ldquo;epithelial-mesenchymal transition\u0026rdquo; (EMT), a key developmental regulatory program, has been reported to play critical and intricate roles in promoting tumor invasion and metastasis in epithelium-derived carcinomas in recent years. Some of the cells undergoing EMT have the characteristics of cancer stem cells (CSCs), which are linked to cancer malignancy (Shibue \u0026amp; Weinberg, 2017; Shihori Tanabe, 2015a, 2015b; Tanabe, Aoyagi, Yokozaki, \u0026amp; Sasaki, 2015). Cancer metastasis and cancer therapeutic resistance are linked to the EMT phenomenon (Smith \u0026amp; Bhowmick, 2016; Tanabe, 2013). EMT causes the cell to escape from the basement membrane and metastasize by increasing the production of enzymes that break down extracellular matrix components and decreasing adherence to the basement membrane (Smith \u0026amp; Bhowmick, 2016).\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-size:14px\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003eOverall Assessment:\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:14px\"\u003eoverall assessment of the AOP was based on the biological domain of the applicability, the essentiality of all KEs, Biological plausibility of each KER, Empirical support for each KER, and Quantitative weight of evidence considerations optional.\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\u003ctable cellspacing=\"0\" class=\"MsoTableGrid\" style=\"border-collapse:collapse; border:none; font-family:\u0026quot;Times New Roman\u0026quot;; font-size:13px; text-align:justify; width:976px\"\u003e\r\n\t\u003ctbody\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:58px\"\u003e\r\n\t\t\t\u003cp\u003e\u0026nbsp;\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:111px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-size:14px\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003eMIE 1669\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:103px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-size:14px\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003eKE 155\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:96px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-size:14px\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003eKE 185\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:101px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-size:14px\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003eKE1980\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:105px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-size:14px\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003eKE1981\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:103px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-size:14px\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003eKE 1172\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:108px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-size:14px\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003eKE 112\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:85px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-size:14px\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003eKE1457\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:104px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-size:14px\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003eAO1982\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:58px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-size:14px\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003eSex/Life stage /Taxa\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:111px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-size:14px\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003eFemale/Reproductive/Human,human cell line,mice,rat\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:103px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-size:14px\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003eFemale/Reproductive/Rat/rat cel lines/mouse\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:96px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-size:14px\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003eFemale/Reproductive/Mice,yeast,hman cel line\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:101px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-size:14px\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003eFemale/Reproductive/canine,mouse,human cell line\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:105px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-size:14px\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003eFemale/Reproductive/human,human cell ine\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:103px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-size:14px\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003eFemale/Reproductive/human,human cell ine,mice\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:108px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-size:14px\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003eFemale/Reproductive/human,human cell ine,mice\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:85px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-size:14px\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003eFemale/Reproductive/hman,hman cell line\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:104px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-size:14px\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003eFemale/Reproductive/hman,hman cell line,mice\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:58px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-size:14px\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003eEssentiality of KEs\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:111px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-size:14px\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003eDirect Evidence\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:103px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-size:14px\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003eDirect Evidence\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:96px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-size:14px\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003eDirect Evidence\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:101px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-size:14px\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003eDirect Evidence\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:105px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-size:14px\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003eDirect Evidence\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:103px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-size:14px\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003eDirect Evidence\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:108px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-size:14px\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003eDirect Evidence\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:85px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-size:14px\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003eDirect Evidence\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:104px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-size:14px\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003eDirect Evidence\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:58px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-size:14px\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003eEmpirical Support of KER\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:111px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-size:14px\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003eHigh for MIE1669 to KE155\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:103px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-size:14px\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003eHigh for KE 155\u0026nbsp;to KE 185\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:96px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-size:14px\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003eModerate for KE 185\u0026nbsp;to KE1980\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:101px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-size:14px\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003eModerate for KE1980\u0026nbsp;to KE1981\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:105px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-size:14px\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003eModerate for KE1981\u0026nbsp;to KE 1172\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:103px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-size:14px\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003eModerate for KE 1172\u0026nbsp;to KE 112\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:108px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-size:14px\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003eHigh for KE 112\u0026nbsp;to KE1457\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:85px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-size:14px\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003eHigh for KE 1457 to AO 1982\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:104px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-size:14px\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e-\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:58px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-size:14px\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003eBiological plausibiity of KER\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:111px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-size:14px\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003eHigh for MIE1669 to KE155\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:103px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-size:14px\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003eHigh for KE 155\u0026nbsp;to KE 185\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:96px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-size:14px\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003eModerate for KE 185\u0026nbsp;to KE1980\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:101px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-size:14px\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003eModerate for KE1980\u0026nbsp;to KE1981\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:105px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-size:14px\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003eModerate for KE1981\u0026nbsp;to KE 1172\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:103px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-size:14px\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003eModerate for KE 1172\u0026nbsp;to KE 112\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:108px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-size:14px\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003eModerate for KE 112\u0026nbsp;to KE1457\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:85px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-size:14px\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003eHigh for KE 1457 to AO 1982\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:104px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-size:14px\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e-\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:58px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-size:14px\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003eQuantitative assessment\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:111px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-size:14px\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003ePCR-RFLP \u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-size:14px\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003eOHdG \u0026ndash; ELISA \u0026amp;RT- PCR, Western Blot \u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-size:14px\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003eMAPK assay, Immunoprecipitation,\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-size:14px\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003eWestern immunoblotting \u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003col start=\"8\"\u003e\r\n\t\t\t\t\u003cli\u003e\u0026nbsp;\u003c/li\u003e\r\n\t\t\t\u003c/ol\u003e\r\n\r\n\t\t\t\u003cp\u003e\u0026nbsp;\u003c/p\u003e\r\n\r\n\t\t\t\u003cp\u003e\u0026nbsp;\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:103px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-size:14px\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003eQuantification of ATase activity \u0026ndash; BSA method\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-size:14px\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003eAPNG assay,\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-size:14px\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003eOXOG glycosylase activity assay,\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-size:14px\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003eWestern immunoblotting,\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-size:14px\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003eImmunohistochemical detection of ATase.\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:96px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-size:14px\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003eAcetaldehyde assay,\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-size:14px\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003eExtract preparation and Western blotting,\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-size:14px\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003eN\u003csup\u003e2\u003c/sup\u003e- Ethyl dGuo quantitation\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp\u003e\u0026nbsp;\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:101px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-size:14px\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003eWestern blotting,clonal survival assay,FACs\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:105px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-size:14px\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003eqRT-PCR,Western blotting,Luciferase reporter assay \u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-size:14px\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003eMicro-array \u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:103px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-size:14px\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003eqRT-PCR,immunohistochemistry \u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp\u003e\u0026nbsp;\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:108px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-size:14px\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003eqRT-PCR, immunohistochemistry ()\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:85px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-size:14px\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003eIHC,micro array,qPCR, SNP array\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:104px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-size:14px\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003eqRT-PCR,,Luciferase reporter assay ,immunoblotting,immunoprecipitation,cell invasion assay,cell migration assay, \u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:58px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-size:14px\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003eReferences\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:111px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-size:14px\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#212121\"\u003eChen CH et al 2011,\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:103px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-size:14px\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#2a2a2a\"\u003ePanida Navasumrit et al, 2001\u003c/span\u003e\u003c/span\u003e),Kotova N et al, 2013,\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#212121\"\u003eGaraycoechea JI et al, 2012\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:96px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-size:14px\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003eAbraham J et al 2011,Garaycoechea JI et al, 2018,Voordeckers K et al, 2020\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:101px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-size:14px\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003evan Jaarsveld MT et al 2014,\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-size:14px\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003eAbdelfattah, N et al, 2018,Liu Z et al, 2017,Zhang X et al,2011\u0026nbsp;Wan G et al, 2013,Bulkowska M et al, 2017\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:105px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-size:14px\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003eShen ZL et al 2016,Guo S et al 2020,Bae HJ et al 2014,Zhou J et al 2017,Fu H et al 2018,,Lian B et al 2018,Guan Y et al 2017,Yang X et al 2014,Jiang G et al 2016,Luo J et al 2017,Tian Z et al 2016,Yan X et al 2019,Zhang S et al 2016\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:103px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-size:14px\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#212121\"\u003eMcGlynn LM et al 2014,\u003c/span\u003e\u003c/span\u003ePaul T. Pfluger et al 2008,\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#212121\"\u003eYeung F et al 2004\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:108px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-size:14px\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003eSampepajung E et al 2021, Van Laere SJ et al 2007,\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-size:14px\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003eSingh S\u0026nbsp;\u0026nbsp;et al 2007,Holloway JN\u0026nbsp;\u0026nbsp;et al 2004,Biswas DK\u0026nbsp;\u0026nbsp;et al 2000,\u0026nbsp;Song RX\u0026nbsp;et al 2005,Scherbakov AM\u0026nbsp;et al 2009,Allred DC and Mohsin SK 2000\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-size:14px\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003eBiswas DK\u0026nbsp;et al 2001\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:85px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-size:14px\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#212121\"\u003eWik E et al 2013,,Bouris P\u003c/span\u003e\u003c/span\u003e\u0026nbsp;et al 2015, \u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#212121\"\u003eLiu Y\u003c/span\u003e\u003c/span\u003e\u0026nbsp;et al 2015,\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#212121\"\u003eAl Saleh S\u003c/span\u003e\u003c/span\u003e\u0026nbsp;et al 2011,\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#212121\"\u003eZeng Q\u003c/span\u003e\u003c/span\u003e\u0026nbsp;et al 2014,\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#212121\"\u003eYe Y\u003c/span\u003e\u003c/span\u003e\u0026nbsp;et al 2010,\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-size:14px\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003eLin, HY\u003c/span\u003e\u003c/span\u003e\u0026nbsp;et al 2018\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\t\u003ctd style=\"border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:104px\"\u003e\r\n\t\t\t\u003cp\u003e\u003cspan style=\"font-size:14px\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003eLiang et al., 2013;Liu et al., 2016;Zhang et al.,2015; Chen et al., 2015;Yue et al.,2019;Wang et al., \u0026nbsp;2018;Yu et al.,2017\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\t\t\t\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\u003c/tbody\u003e\r\n\u003c/table\u003e\r\n","background":"\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12pt\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eAlcoholic beverages are classified by the International Agency for Research on Cancer(IARC) as Group 1 carcinogens. Studies have reported alcohol consumption to be a\u0026nbsp; risk factor for breast cancer in women(\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003eRoom R\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003e\u0026nbsp;et al\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003e,\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003e\u0026nbsp;2005)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e. A woman drinking an average of two units of alcohol per day has an 8% higher risk of developing breast cancer than a woman who drinks an average of one unit of alcohol per day[2]. Alcohol is metabolized by alcohol dehydrogenase to acetaldehyde which is a mutagen. Various theories have been proposed which explain the mutagenicity of alcohol. Among them, the most relevant one for carcinoma of the breast has been proposed by Purohita et al, suggesting an alcohol-induced inactivation of the tumor suppressor gene BRCA1 and increased estrogen\u0026nbsp;Responsiveness in breast tissues\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e(\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003ePurohit V\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003e\u0026nbsp;et al, 2005)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e. Boffetta and Hashibe list plausible mechanisms of breast cancer as a result of the genotoxic effect of acetaldehyde-induced increased estrogen concentration\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e(\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003eBoffetta P\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003e\u0026nbsp;et al 2006)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e.\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"color:#222222\"\u003e\u0026nbsp;It has also been found that alcohol stimulates the \u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eepithelial-mesenchymal transition (EMT), because of which there is distant metastasis \u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e(\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003eForsyth C. B.\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003e\u0026nbsp;et al 2010)\u003c/span\u003e\u003c/span\u003e. However, this mechanism needs to be elucidated in detail.\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12pt\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eMicroRNAs (miRNAs) are non-coding, single-stranded RNA molecules that regulate target gene expression via post-transcriptional modifications [\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003eMohr A. M\u0026amp; Mott J. L 201\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003e5 and \u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003eLai\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u0026nbsp;\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003eE. C. 2002\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003e)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e. Several studies indicated the promising role of miRNA in the diagnosis and outcome prediction in several cancers \u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e(\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003eMirzaei H\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003e\u0026nbsp;et al 2018 and \u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003eLiu, S. Y\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003e\u0026nbsp;et al 2017)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e. miRNA-21 is upregulated and promotes metastasis in several cancers \u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e(\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003eKunita, A\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003e\u0026nbsp;et al 2018 and\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003eLiu Z\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003e\u0026nbsp;et al 2015)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e. A Chinese study by Kunita et al proved that plasma levels of miRNA\u0026nbsp;were up-regulated in large B-cell lymphoma patients \u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e(\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003eKunita, A\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003e\u0026nbsp;et al 2018)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e. A study\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"color:#131413\"\u003e\u0026nbsp;by Wang et al also proved that plasma levels of miR\u0026nbsp;were upregulated in large B-cell lymphoma patients in China \u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"color:#131413\"\u003e(\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eChen et al 2014)\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"color:#131413\"\u003e. Although miR-21 was indicated to play a crucial role in the metastasis of lung cancer, ovarian cancer, and head and neck cancer through several signaling pathways, the molecular mechanism of how miR-21 regulates the EMT process in breast cancer is not clear \u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"color:#131413\"\u003e(\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003eLiu S. Y\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003e\u0026nbsp;et al, \u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003eLopez-Santillan\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003e\u0026nbsp;et al 2018, \u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003ePanagal M.\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003e\u0026nbsp;et al 2018, \u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003eZhou, B.\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003eet al 2018, \u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003eBrabletz T\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003e\u0026nbsp;et al and \u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003eYe, X.\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003e\u0026nbsp;et al 2017)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"color:#131413\"\u003e.There are a number of miRNAs which regulate SIRT 1 expression.\u0026nbsp;The epithelial-mesenchymal transition (EMT) is a process that which epithelial cells lose their cell polarity and cell adhesion ability, which will lead to cancer metastasis \u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"color:#131413\"\u003e(\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003eVaziri H\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003e\u0026nbsp;et al 2001 and \u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003eLuo, J\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003e\u0026nbsp;et al 2001)\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"color:#131413\"\u003e. Epithelial cells exhibit the property of regular cell-cell contacts, adhesion to the surrounding cellular fabric, preventing the detachment of individual cells. Whereas mesenchymal cells do not form intercellular contacts.\u0026nbsp; \u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12pt\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"color:#000000\"\u003eSirtuins are nicotinamide adenine dinucleotide (NAD+)\u0026ndash;dependent deacetylases that function as intracellular regulators of transcriptional activity (\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003eBlander G \u0026amp; Guarente L 2004\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003e\u0026nbsp;and \u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003eRoth M \u0026amp; Chen W 2014\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003e)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"color:#000000\"\u003e. It plays important roles in cell survival, signal transduction, and cell apoptosis by deacetylating key cell signaling molecules and apoptotic related proteins, such as NF-kB, p53, Ku70, and HIFs \u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"color:#000000\"\u003e(\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003eZhao, W\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003e\u0026nbsp;et al 2008 and \u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003eChen W \u0026amp; Bhatia R\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u0026nbsp;\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003e2013\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003e)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"color:#000000\"\u003e. Various studies have inconclusive reports\u003c/span\u003e\u003c/span\u003e\u0026nbsp;\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"color:#000000\"\u003eon the role of SIRT1 in cancer, because of its opposite effects as both a tumor activator or suppressor in various human cancers, including breast cancer.\u0026nbsp; Deng et al found that the expression of SIRT1 was lower in prostate cancer, bladder cancer, ovarian cancer, and glioblastoma when compared with normal tissues \u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"color:#000000\"\u003e(\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003eHan, L\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003e\u0026nbsp;et al 2013)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"color:#000000\"\u003e.On the contrary, it was found that, in leukemia and lung cancer, SIRT1 was significantly higher\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"color:#000000\"\u003e(\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003eRiggio M\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003e\u0026nbsp;et al 2012 and \u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003eLee M S\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003e\u0026nbsp;et al 2015)\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"color:#000000\"\u003e. \u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12pt\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#000000\"\u003eThis can be explained as follows: SIRT1-mediated deacetylation suppresses the functions of several tumor suppressors including p53, p73, and HIC1, it has been suggested that SIRT1 has a promoting function in tumor development and progression [\u003c/span\u003e\u003cspan style=\"color:#222222\"\u003ePinton G\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003e\u0026nbsp;et al 2016, \u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003ePillai VB\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003e\u0026nbsp;\u0026nbsp;et al 2014, \u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003eWan G\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003e\u0026nbsp;et al 2017 and \u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003eHwang B\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003e\u0026nbsp;et al 2014\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#000000\"\u003e].\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u0026nbsp;\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#000000\"\u003eIn contrast, SIRT1 may have a suppressive activity in tumor cell growth by suppressing NF-\u0026kappa;B,\u0026nbsp;a transcription factor playing a central role in the regulation of the innate and adaptive immune responses and carcinogenesis, the dysregulation of which leads to the onset of tumorigenesis and tumor malignancy\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#000000\"\u003e(\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003eYuan J\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003e\u0026nbsp;et al 2009, \u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003eWang R H\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003e\u0026nbsp;et al 2008, \u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003eChen L F\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003e\u0026nbsp;et al 2004 and \u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003eGreten F R \u0026amp; Karin M 2004\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003e)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#000000\"\u003e.\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u0026nbsp;\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"color:#000000\"\u003eHere, we aim to further explore the role of the SIRT1-NF kB signaling pathway in tumorigenesis\u003c/span\u003e\u003c/span\u003e\u0026nbsp;\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"color:#000000\"\u003eof the breast as well as its associated mechanisms.\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12pt\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"color:#131413\"\u003eThe nuclear factor-\u0026kappa;B (NF- \u0026kappa;B)/REL family of transcription factors is comprised of a RELA/p65,c-REL, RELB, p105/NF- \u0026kappa;B1 and p100/NF- \u0026kappa;B2 (\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003eVan Laere S J\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003e\u0026nbsp;et al 2007)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"color:#131413\"\u003e. The p105 and p100 proteins can be processed by proteolytic cleavage into p50 and p52, respectively. Activation of the NF-\u0026kappa;B signaling pathway leads to the induction of target genes that can inhibit apoptosis, interaction with cell cycle regulation, cell invasion, contribute to tumorigenesis and metastatic invasion \u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"color:#131413\"\u003e(\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003eShostak K \u0026amp; Chariot 2011\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003e)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"color:#131413\"\u003e. Activation NF-\u0026kappa;B in breast cancer is loss of Estrogen Receptor (ER) expression and Human Epidermal Growth Factor Receptor 2 (HER-2) overexpressed via epidermal growth factor receptor (EGFR) and Mitogen-Activated Protein Kinase (MAPK) pathway \u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"color:#131413\"\u003e(\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003eAli S \u0026amp; Coombes R C\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u0026nbsp;\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003e2002\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003e)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"color:#131413\"\u003e. Indeed, the binding of epidermal growth factor (EGF) to its receptor (EGFR) also ultimately activates NF-\u0026kappa;B and most likely contributes to the enhanced activity of this transcription factor in ER-negative breast cancer cells \u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"color:#131413\"\u003e(\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003eKalkhoven E\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003e\u0026nbsp;et al 1996)\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"color:#131413\"\u003e. \u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12pt\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"color:#131413\"\u003eLoss of ER function has been associated with constitutive NFkB activity and hyperactive MAPK, because of constitutive secretion of cytokine and growth factors, which ultimately culminates in aggressive, metastatic, hormone-resistant cancers (\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003eMerkhofer E C\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003e\u0026nbsp;et al 2010)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"color:#131413\"\u003e. Activation of the progesterone receptor can lead to inhibition of NF-\u0026kappa;B driven gene expression \u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"color:#131413\"\u003e(\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003eSethi G\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003e\u0026nbsp;et al 2008\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"color:#131413\"\u003e)\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"color:#131413\"\u003e\u0026nbsp;reducing its DNA binding and transcriptional activity. HER-2 activates NF-\u0026kappa;B through the canonical pathway which surprisingly, involves IKK\u0026alpha; \u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"color:#131413\"\u003e(\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003eIto, T\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003e\u0026nbsp;et al 2010)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"color:#131413\"\u003e. Activation of NF-\u0026kappa;B promotes the survival of tumor cells. Several gene products that negatively regulate apoptosis in tumor cells are controlled by NF-\u0026kappa;B activation \u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"color:#131413\"\u003e(\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003eLee J\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003e\u0026nbsp;et al 2010\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"color:#131413\"\u003e)\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"color:#131413\"\u003e. Estrogen plays an important role in breast cancer initiation and progression. Breast cancer over time acquires different mutations and the proportion of estrogen receptor-negative cells in tumors increases. This transformation confers aggressive biological characteristics to breast cancer such as rapid growth, poor differentiation, and poor response to hormone therapy. NF-\u0026kappa;B pathway plays important role in this pathway \u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"color:#131413\"\u003e(\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003eLee J\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003e\u0026nbsp;et al 2010\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"color:#131413\"\u003e). \u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12pt\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eExpression of SIRT1 is controlled at multiple levels by transcriptional, post-transcriptional, and post-translational mechanisms under physiological and pathological conditions. Emerging evidence indicates that miRs are important regulators of SIRT1 expression (\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003eLovis P\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003e\u0026nbsp;et al 2008,\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003eOrtega F J\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003e\u0026nbsp;et al 2010, \u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003eZovoilis A\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003e\u0026nbsp;et al 2011, \u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003eYamakuchi M\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003e\u0026nbsp;et al 2008 and \u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003eMullany L E\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003e\u0026nbsp;et al 2017)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e. Studies have shown that miR-34a directly binds to the 3\u0026prime; untranslated region (UTR) of SIRT1 mRNA and reduces its expression \u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e(\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003eOrtega F J\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003e\u0026nbsp;et al 2010)\u003c/span\u003e\u003c/span\u003e. \u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\u003cp style=\"text-align:justify\"\u003e\u003cspan style=\"font-family:Arial,Helvetica,sans-serif\"\u003e\u003cspan style=\"font-size:12pt\"\u003e\u003cspan style=\"font-size:12.0000pt\"\u003eStudy findings support the hypothesis that alcohol consumption is able to influence miRNA expression.\u003c/span\u003e\u0026nbsp;\u003cspan style=\"font-size:12.0000pt\"\u003eConsiderable evidence from rodent and human studies demonstrates that disruption of the hepatic SIRT1 signaling by ethanol plays a central role in the development of AFLD \u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e(\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003eYin H\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003e\u0026nbsp;et al 2014, \u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003eLi M\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003e\u0026nbsp;et al 2014)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e.Ethanol down-regulates SIRT1 in hepatic cells and in the animal livers. The ethanol-mediated disruption of SIRT1 signaling leads to excess fat accumulation and inflammatory responses in the liver of animals and humans. Treatment with resveratrol, a known SIRT1 agonist, can alleviate liver steatosis . Accumulating evidence demonstrates that ethanol-mediated SIRT1 inhibition leads to the development of AFLD largely through disruption of a signaling network mediated by various transcriptional regulators and co-regulators, including nuclear transcription factor-\u0026kappa;B (NF-\u0026kappa;B)\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e(\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003eYin H\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003e\u0026nbsp;et al 2014, \u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003eLi M\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:12.0000pt\"\u003e\u003cspan style=\"background-color:#ffffff\"\u003e\u003cspan style=\"color:#222222\"\u003e\u0026nbsp;et al 2014)\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n","user_defined_mie":null,"user_defined_ao":null,"oecd_project":"1.103","oecd_status_id":4,"graphical_representation_image_uid":"2022/08/14/zwe78w3og_AOP_diagram_new.jpg","saaop_status_id":1,"legacy":false,"overall_assessment_file_uid":null,"changed_at":"2022-08-14T08:30:53.000-04:00","development_strategy":"\u003cp\u003e\u003cspan style=\"font-size:11pt\"\u003e\u003cspan style=\"font-family:Calibri,sans-serif\"\u003eIn the context of the OECD (Organization for Economic Co-operation and Development) Adverse Outcome Pathway (AOP) Handbook, Key Events (KEs) are critical steps that occur in a sequence leading from a molecular initiating event (MIE) to an adverse outcome. Essentiality of KEs refers to demonstrating that a particular key event is necessary for the overall progression of the pathway and the eventual manifestation of the adverse outcome. Here\u0026#39;s how we can support for the essentiality of the KEs in accordance with the OECD AOP Handbook:\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003cspan style=\"font-size:11pt\"\u003e\u003cspan style=\"font-family:Calibri,sans-serif\"\u003e1.Identify the Key Events (KEs): Clearly state the key events in the sequence that leads from the initial molecular event to the adverse outcome. These key events should reflect the critical steps that are believed to be involved in the pathway.\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003cspan style=\"font-size:11pt\"\u003e\u003cspan style=\"font-family:Calibri,sans-serif\"\u003e2.Biological Plausibility: Explain the biological rationale and scientific evidence supporting each key event. This should include mechanistic understanding of how each key event contributes to the overall pathway. Provide information on relevant biological processes, molecular interactions, and any existing knowledge in the literature that supports the occurrence of these events.\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003cspan style=\"font-size:11pt\"\u003e\u003cspan style=\"font-family:Calibri,sans-serif\"\u003e3. Empirical Evidence: Describe any experimental data or studies that directly demonstrate the occurrence of each key event. This can include in vitro studies, animal models, human data, or any other relevant research that provides evidence for the occurrence of these events in response to the molecular initiating event.\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003cspan style=\"font-size:11pt\"\u003e\u003cspan style=\"font-family:Calibri,sans-serif\"\u003e4. Temporal Relationship: Discuss the temporal relationship between each key event and its position in the pathway. Explain how the occurrence of one key event leads to the initiation or occurrence of the subsequent key event. This demonstrates the sequential progression of events leading to the adverse outcome.\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003cspan style=\"font-size:11pt\"\u003e\u003cspan style=\"font-family:Calibri,sans-serif\"\u003e5. Dose-Response Relationship: If available, provide information on the dose-response relationship between the molecular initiating event and the subsequent key events. This can strengthen the argument for the essentiality of each key event by showing that changes in the dose of the initiating event correspond to changes in the occurrence of the key events.\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003cspan style=\"font-size:11pt\"\u003e\u003cspan style=\"font-family:Calibri,sans-serif\"\u003e6. Concordance in Different Systems: If possible, highlight how the key events have been observed across different biological systems, species, or experimental conditions. Consistency in the occurrence of key events in diverse settings reinforces their essentiality in the pathway.\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003cspan style=\"font-size:11pt\"\u003e\u003cspan style=\"font-family:Calibri,sans-serif\"\u003e7. Counter Evidence or Uncertainties: Acknowledge any counter evidence or uncertainties related to the essentiality of the key events. Address any conflicting data or alternative explanations that have been proposed in the literature.\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n\r\n\u003cp\u003e\u003cspan style=\"font-size:11pt\"\u003e\u003cspan style=\"font-family:Calibri,sans-serif\"\u003e8. Overall AOP Plausibility: Summarize the overall plausibility of the AOP, emphasizing the role of each key event in the pathway. Explain how the sequence of events is coherent, biologically reasonable, and well-supported by available evidence.\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:11pt\"\u003e\u003cspan style=\"font-family:Calibri,sans-serif\"\u003eBy providing a comprehensive overview of the biological rationale, empirical evidence, and logical progression of key events in the AOP, we have effectively support the essentiality of these events in accordance with the OECD AOP Handbook.\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\r\n","known_modulating_factors":"\u003cdiv\u003e\r\n\u003ctable class=\"table table-bordered table-fullwidth\"\u003e\r\n\t\u003cthead\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003cth\u003eModulating Factor (MF)\u003c/th\u003e\r\n\t\t\t\u003cth\u003eInfluence or Outcome\u003c/th\u003e\r\n\t\t\t\u003cth\u003eKER(s) involved\u003c/th\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\u003c/thead\u003e\r\n\t\u003ctbody\u003e\r\n\t\t\u003ctr\u003e\r\n\t\t\t\u003ctd\u003e\u0026nbsp;\u003c/td\u003e\r\n\t\t\t\u003ctd\u003e\u0026nbsp;\u003c/td\u003e\r\n\t\t\t\u003ctd\u003e\u0026nbsp;\u003c/td\u003e\r\n\t\t\u003c/tr\u003e\r\n\t\u003c/tbody\u003e\r\n\u003c/table\u003e\r\n\u003c/div\u003e\r\n","assigned_license_id":389,"handbook_id":2,"project_129":false}],"pagination":{"current_page":1,"per_page":25,"total_entries":6,"total_pages":1}}