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Increased pro-inflammatory mediators leads to N/A, Breast Cancer
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|Increased reactive oxygen and nitrogen species (RONS) leading to increased risk of breast cancer||adjacent||Moderate||Not Specified||Jessica Helm (send email)||Under development: Not open for comment. Do not cite||Under Development|
|Increased DNA damage leading to increased risk of breast cancer||adjacent||Moderate||Not Specified||Jessica Helm (send email)||Under development: Not open for comment. Do not cite||Under Development|
Life Stage Applicability
Key Event Relationship Description
Pro-inflammatory mediators increase the risk of breast cancer.
Evidence Collection Strategy
Evidence Supporting this KER
Biological Plausibility is Moderate. 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.
Empirical Evidence is Moderate. 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 (including EMT and senescence) following IR or stimulation of inflammatory pathways. However, the key event and the adverse outcome differ in their dose-response to ionizing radiation: inflammation does not increase linearly with dose, while breast cancer and invasion does. Uncertainty arises from differences between the CBA/Ca mouse susceptible to leukemia from IR and the BALB/c mouse susceptible to mammary tumors from IR- the former has a pro-inflammatory response while the latter is apparently a mix of anti- and pro-inflammatory. This is a reminder that both pro- and anti-inflammatory factors may contribute to carcinogenesis- further research will be required to identify the context for each.
Biological Plausibility is Moderate. 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. Studies suggest carcinogenic effects of IR extend beyond DNA damage and mutation of directly affected cells (Bouchard, Bouvette et al. 2013; Sridharan, Asaithamby et al. 2015; Barcellos-Hoff and Mao 2016), including indirect effects through exposed stroma of mammary gland (Nguyen, Oketch-Rabah et al. 2011; Nguyen, Fredlund et al. 2013; Illa-Bochaca, Ouyang et al. 2014). Inflammatory reactions offer one possible mechanism. Tumors 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).
In photocarcinogenesis, cytokines and inflammatory signaling are implicated in immunosuppression and in promoting DNA damage via RONS (Valejo Coelho, Matos et al. 2016). In addition, inflammation related NF-kB, STAT3, COX2 and prostaglandins are implicated in the development and proliferation of skin cancers (Martens, Seebode et al. 2018).
Multiple cytokines and inflammatory pathways are implicated in mammary tumors and breast cancer. Cytokines TGF-b and IL6 transform 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). IL6 is expressed by breast cancer fibroblasts and by fibroblasts from common sites of breast metastasis (breast, lung, and bone). IL6 is required for the growth and tumor promoting effects of fibroblasts from these sites on ER-positive (MCF-7) cancer cells in vitro and in vivo. IL6 can also promote the expression of IL6 in senescent (skin) fibroblasts and pre-malignant ER- breast epithelial cells (MCF10A). (Sasser, Sullivan et al. 2007; Studebaker, Storci et al. 2008). The growth and invasion-promoting effects of IL6 on primary non-cancer and cancer cell line (MCF-7) mammospheres in vitro depends on the activity of transcription factor NOTCH3, which supports the renewal of stem-like cell populations (Sansone, Storci et al. 2007). The inflammation-related transcription factor NF-kB contributes to mammary tumorigenesis and metastasis in PyVt mice (Connelly, Barham et al. 2011), and NF-kB/IL6/STAT3 activation is essential to mammosphere formation and migration in vitro as well as tumorigenesis from Src-activated or IL6 transformed MCF10 cells (Iliopoulos, Hirsch et al. 2009). The NF-kB/IL6/STAT3 signaling pathway generates cancer stem cells in multiple types of breast cancer cells lines and primary 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).
Uncertainties and Inconsistencies
Uncertainty arises from the multifunctional nature of TGF-β, which may be anti- or pro-carcinogenic based on context, and around the contribution of inflammatory macrophages, which can differ based on genetic background. Further research is needed to isolate and identify the critical factors in these responses and their application in mammary gland.
TGF-β can be protective in a developmental context but may increase risk in another context. Increased baseline TGF-β decreases tumor incidence following lower doses of IR (0.1 Gy) in the SPRET outbred mouse, possibly by reducing ductal branching during development and subsequent susceptibility (Zhang, Lo et al. 2015). Conversely, the BALB/c mouse has lower baseline TGF-β during development but is susceptible to mammary tumors after IR, possibly via an elevated TGF-β response to IR. Early (4 hours) after low dose (0.075 Gy) IR these mice have suppressed immune pathways and macrophage response but increased IL6, COX2, and TGF-β pathway activation in mammary gland compared to the tumor-resistant C57BL/6 mouse (Snijders, Marchetti et al. 2012; Bouchard, Bouvette et al. 2013). By 1 week after IR BALB/c mammary glands show TGF-β-dependent inflammation, and by 1 month after IR they show proliferation (Nguyen, Martinez-Ruiz et al. 2011; Snijders, Marchetti et al. 2012). Consistent with this pattern, BALB/c mice that are heterozygous for TGF-β are more resistant to mammary tumorigenesis following IR (Nguyen, Oketch-Rabah et al. 2011). This pattern suggests that TGF-β is associated with inflammation, proliferation, and mammary tumorigenesis in these mice. 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.
Genetically susceptible mouse models offer somewhat conflicting information about the contribution of inflammation to cancer. In the CBA/Ca mouse susceptible to leukemia the macrophage response to IR is pro-inflammatory (M1 type) in contrast to the mammary tumor resistant C57BL/6 mouse, which develops anti-inflammatory M2type pro-phagocytic oxidative macrophages that target apoptotic cells (Lorimore, Coates et al. 2001; Lorimore, Chrystal et al. 2008). In contrast, in the BALB/c mouse susceptible to mammary tumors many inflammatory pathways and macrophages are suppressed early after IR, although there is also evidence of inflammation especially at later points (Nguyen, Martinez-Ruiz et al. 2011; Snijders, Marchetti et al. 2012; Bouchard, Bouvette et al. 2013). It is possible that the two carcinogenic models represent two different mechanisms of susceptibility.
Finally, inflammation and other stromal factors alone are not sufficient to produce breast cancer. Studies in mice that support the importance of stromal context to IR tumorigenesis used epithelial cells with mutations in a DNA damage response gene p53. These transplant studies irradiate a mammary gland fat pad with epithelial cells removed, and transplant non-irradiated pre-malignant mutant (typically p53 mutant) epithelial cells (Barcellos-Hoff and Ravani 2000; Nguyen, Oketch-Rabah et al. 2011). Similar experiments showing NMU-treated stromal promotion of tumorigenesis use untreated primary epithelial cells sub-cultured repeatedly in vitro where some initiation could have taken place (Maffini, Soto et al. 2004), while in a similar experiment DMBA-treated stroma does not cause tumors from transplanted pre-malignant immortal cells (Medina and Kittrell 2005). This dependence on both stromal context and mutations to DNA damage response is consistent with contemporary ideas about the multi-factorial nature of carcinogenesis.
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
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Andarawewa, K. L., A. C. Erickson, et al. (2007). "Ionizing radiation predisposes nonmalignant human mammary epithelial cells to undergo transforming growth factor beta induced epithelial to mesenchymal transition." Cancer Res 67(18): 8662-8670.
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Ebrahimian, T. G., L. Beugnies, et al. (2018). "Chronic Exposure to External Low-Dose Gamma Radiation Induces an Increase in Anti-inflammatory and Anti-oxidative Parameters Resulting in Atherosclerotic Plaque Size Reduction in ApoE(-/-) Mice." Radiation research 189(2): 187-196.
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El-Saghire, H., H. Thierens, et al. (2013). "Gene set enrichment analysis highlights different gene expression profiles in whole blood samples X-irradiated with low and high doses." Int J Radiat Biol 89(8): 628-638.
Iliopoulos, D., H. A. Hirsch, et al. (2011). "Inducible formation of breast cancer stem cells and their dynamic equilibrium with non-stem cancer cells via IL6 secretion." Proceedings of the National Academy of Sciences of the United States of America 108(4): 1397-1402.
Kim, E. S., M. S. Kim, et al. (2004). "TGF-beta-induced upregulation of MMP-2 and MMP-9 depends on p38 MAPK, but not ERK signaling in MCF10A human breast epithelial cells." Int J Oncol 25(5): 1375-1382.
Liakou, E., E. Mavrogonatou, et al. (2016). "Ionizing radiation-mediated premature senescence and paracrine interactions with cancer cells enhance the expression of syndecan 1 in human breast stromal fibroblasts: the role of TGF-beta." Aging (Albany NY) 8(8): 1650-1669.
Lorimore, S. A., J. A. Chrystal, et al. (2008). "Chromosomal instability in unirradiated hemaopoietic cells induced by macrophages exposed in vivo to ionizing radiation." Cancer Res 68(19): 8122-8126.
Lorimore, S. A., P. J. Coates, et al. (2001). "Inflammatory-type responses after exposure to ionizing radiation in vivo: a mechanism for radiation-induced bystander effects?" Oncogene 20(48): 7085-7095.
Monceau, V., L. Meziani, et al. (2013). "Enhanced sensitivity to low dose irradiation of ApoE-/- mice mediated by early pro-inflammatory profile and delayed activation of the TGFbeta1 cascade involved in fibrogenesis." PLoS One 8(2): e57052.
Natarajan, M., C. F. Gibbons, et al. (2007). "Oxidative stress signalling: a potential mediator of tumour necrosis factor alpha-induced genomic instability in primary vascular endothelial cells." Br J Radiol 80 Spec No 1: S13-22.
Nguyen, D. H., H. A. Oketch-Rabah, et al. (2011). "Radiation acts on the microenvironment to affect breast carcinogenesis by distinct mechanisms that decrease cancer latency and affect tumor type." Cancer Cell 19(5): 640-651.
Sasser, A. K., N. J. Sullivan, et al. (2007). "Interleukin-6 is a potent growth factor for ER-alpha-positive human breast cancer." FASEB journal : official publication of the Federation of American Societies for Experimental Biology 21(13): 3763-3770.
Snijders, A. M., F. Marchetti, et al. (2012). "Genetic differences in transcript responses to low-dose ionizing radiation identify tissue functions associated with breast cancer susceptibility." PLoS One 7(10): e45394.
Studebaker, A. W., G. Storci, et al. (2008). "Fibroblasts isolated from common sites of breast cancer metastasis enhance cancer cell growth rates and invasiveness in an interleukin-6-dependent manner." Cancer Res 68(21): 9087-9095.
Yu, Y., R. Okayasu, et al. (2001). "Elevated breast cancer risk in irradiated BALB/c mice associates with unique functional polymorphism of the Prkdc (DNA-dependent protein kinase catalytic subunit) gene." Cancer Res 61(5): 1820-1824.