Stressor: 451

Title

To create a new stressor, from the Listing Stressors page at https://aopwiki.org/stressors click ‘New stressor.’ This will bring you to a page entitled “New Stressor” where a stressor title can be entered. Click ‘Create stressor’ to create a new Stressor page listing the stressor title at the top. More help

Ionizing Radiation

Stressor Overview

The stressor field is a structured data field that can be used to annotate an AOP with standardised terms identifying stressors known to trigger the MIE/AOP. Most often these are chemical names selected from established chemical ontologies. However, depending on the information available, this could also refer to chemical categories (i.e., groups of chemicals with defined structural features known to trigger the MIE). It can also include non-chemical stressors such as genetic or environmental factors. More help

AOPs Including This Stressor

This table is automatically generated and lists the AOPs associated with this Stressor. More help

AOP Name	Evidence
Increased DNA damage leading to increased risk of breast cancer	High
Increased reactive oxygen and nitrogen species (RONS) leading to increased risk of breast cancer	High
Oxidative DNA damage leading to chromosomal aberrations and mutations	High
Direct deposition of ionizing energy leading to lung cancer	High
Chronic reactive oxygen species leading to human treatment-resistant gastric cancer	Moderate

Events Including This Stressor

This table is automatically generated and lists the Key Events associated with this Stressor. More help

Event Name
Increase in reactive oxygen and nitrogen species (RONS)
Increase, DNA damage
Increase, Cell Proliferation (Epithelial Cells)
Increase, Oxidative damage to DNA
Increase, DNA strand breaks
Increase, Cell Proliferation
Direct Deposition of Energy
N/A, Inadequate DNA repair
Increase, Mutations
Increase, Chromosomal aberrations
Increase, lung cancer
Chronic reactive oxygen species

Chemical Table

The Chemical Table lists chemicals associated with a stressor. This table contains information about the User’s term for a chemical, the DTXID, Preferred name, CAS number, JChem InChIKey, and Indigo InChIKey.To add a chemical associated with a particular stressor, next to the Chemical Table click ‘Add chemical.’ This will redirect you to a page entitled “New Stressor Chemical.’ The dialog box can be used to search for chemical by name, CAS number, JChem InChIKey, and Indigo InChIKey. Searching by these fields will bring forward a drop down list of existing stressor chemicals formatted as Preferred name, “CAS- preferred name,” “JChem InChIKey – preferred name,” or “Indigo InChIKey- preferred name,” depending on by which field you perform the search. It may take several moments for the drop down list to display. Select an entity from the drop down list and click ‘Add chemical.’ This will return you to the Stressor Page, where the new record should be in the ‘Chemical Table’ on the page.To remove a chemical associated with a particular stressor, in the Chemical Table next to the chemical you wish to delete, click ‘Remove’ and then click 'OK.' The chemical should no longer be visible in the Chemical table. More help

AOP Evidence

This table is automatically generated and includes the AOPs with this associated stressor as well as the evidence term and evidence text from this AOP Stressor. More help

Increased DNA damage leading to increased risk of breast cancer

Human

Exposure to ionizing radiation is a well-established risk factor for breast cancer in people. Ionizing radiation increases the risk of death from breast cancer and other solid cancers, particularly bladder and renal cancers, as well as leukemia and other blood cancers (Ozasa, Shimizu et al. 2012). Much of the evidence for breast cancer following radiation in humans comes from therapeutic or diagnostic (typically low LET) radiation and from the atomic bombs in Japan, which released a radiation mixture featuring low LET gamma but also neutron radiation (Preston, Mattsson et al. 2002). Epidemiologic studies of women exposed to the atomic bomb in Japan (Little and McElvenny 2017), to therapeutic radiation for benign disorders (Eidemuller, Holmberg et al. 2015), childhood cancer (Henderson, Amsterdam et al. 2010; Moskowitz, Chou et al. 2014), or contralateral breast cancer (Neta, Anderson et al. 2012), or to frequent chest X-rays including TB fluoroscopy (Ma, Hill et al. 2008; Bijwaard, Brenner et al. 2010) all show a significant increase of breast cancer risk with radiation exposure.

Rodent

Rodents can be used to study mammary gland carcinogenesis in response to ionizing radiation, but formation of mammary tumors in rodents in response to ionizing radiation varies by species and by strain. Mammary tumors are common in rats (Russo 2015) and ionizing radiation increases the incidence of mammary tumors, although sensitivity to radiation varies by strain (Imaoka, Nishimura et al. 2009). Mammary tumors are rare in mice (Wagner 2004), leading to the use of genetically sensitive strains and tumor promoting viruses to study mammary tumors in mice (Wagner 2004; Russo 2015). The BALB/c mouse has a higher baseline rate of mammary tumors, and in this strain ionizing radiation increases the incidence of mammary tumors (Imaoka, Nishimura et al. 2009; Rivina, Davoren et al. 2016).

Modifying factors

Age

Women exposed to therapeutic doses of ionizing radiation at younger ages are more susceptible to breast cancer from ionizing radiation than women exposed later in life (Miller, Howe et al. 1989; Boice, Preston et al. 1991; Ma, Hill et al. 2008; Stovall, Smith et al. 2008; Berrington de Gonzalez, Curtis et al. 2010). Studies of atomic bomb survivors also show higher risk of breast cancer with decreasing age at the time of the bombing, although different models result in different conclusions about whether age at exposure acts additively (Land, Tokunaga et al. 2003) or multiplicatively (Preston, Ron et al. 2007) with regard to other breast cancer risk factors.

The stage of development at ionizing radiation exposure is also important in animals. Risk appears to be highest for IR exposures between one and seven weeks during mammary gland development and puberty (Imaoka, Nishimura et al. 2011; Imaoka, Nishimura et al. 2013; Imaoka, Nishimura et al. 2017) with lower rates in embryonic, adult (Imaoka, Nishimura et al. 2011; Imaoka, Nishimura et al. 2013), and post-estrous rats (Bartstra, Bentvelzen et al. 1998). As in humans, studies of pre-pubertal risk in animals may be affected by the impact of whole body radiation on ovaries, leading to decreased circulating reproductive hormones (Imaoka, Nishimura et al. 2011).

The effect of age is thought to be related to developmental changes occurring in the breast with puberty and with childbirth and breast feeding. The growth and development of the epithelial portion of the breast that will eventually produce and deliver milk is limited until the onset of puberty (Sternlicht, Sunnarborg et al. 2005). Undifferentiated stem cells proliferate at puberty and expand into the stroma to form branched structures and terminal ducts (Hinck and Silberstein 2005; Sternlicht, Sunnarborg et al. 2005). Stem cells are thought to be more capable of forming tumors because their long lifespan makes it more likely that they will sustain multiple mutagenic hits, frequent mitosis increases the likelihood of mutation, and because they are capable of passing any mutations on to multiple progeny which can then acquire further mutations (Imaoka, Nishimura et al. 2009; Russo 2015). Thus puberty brings an expansion in the number of vulnerable cells. Development continues to a lesser degree after puberty with each menstrual cycle.

Pregnancy or parity is protective against breast cancer from radiation. Early age of pregnancy acted multiplicatively to reduce risk from the atomic bomb (Land, Hayakawa et al. 1994), and women who have never gone through childbirth (and the associated breast differentiation) before radiation exposure have an increased risk of contralateral breast cancer from ionizing radiation while no significant increase is seen among parous women (Brooks, Boice et al. 2012). This decrease in risk of IR exposure with parity is consistent with breast cancer risk in the general population- risk of (ER+) breast cancer is higher in older women who have never had a child and lower for women who have had one or more children (after an initial increase around childbirth) (Britt, Ashworth et al. 2007; Ma, Henderson et al. 2010; Dall, Risbridger et al. 2017).

The rodent literature on IR does not offer a clear parallel to the epidemiological data, with animal exposures occurring only during or shortly after pregnancy. Rats are more sensitive to mammary cancer following IR during or shortly after pregnancy compared with virgin mice. Several studies find that cancer incidence is higher in animals exposed to ionizing radiation while pregnant and lactating (Inano, Suzuki et al. 1991; Suzuki, Ishii-Ohba et al. 1994; Inano, Suzuki et al. 1996). Post-lactational extracellular matrix also supports the metastasis of transplanted tumors (McDaniel, Rumer et al. 2006), although an early study did not report a difference in tumor incidence between virgin, pregnant, lactating, and post-lactational rats exposed to IR (Holtzman, Stone et al. 1982). However, parity is protective against spontaneous and carcinogen-induced mammary tumors in rodents (Britt, Ashworth et al. 2007; Rajkumar, Kittrell et al. 2007; Dall, Risbridger et al. 2017).

The protective effect of parity observed in humans and in spontaneous and carcinogen-induced mammary tumors is again attributed to the development and differentiation of susceptible stem cells in the breast. Proliferation increases dramatically during pregnancy before a major terminal differentiation leading to lactation (Oakes, Hilton et al. 2006; Anderson, Rudolph et al. 2007). This process is coupled with a decline in hormone sensing epithelial cells and stem cells in the mammary gland (Dall, Risbridger et al. 2017). Conversely, this pregnancy-related decrease in hormone sensing and stem cells does not apply to first pregnancies at older ages and may explain the lack of protection afforded by first parity in older women (Dall, Risbridger et al. 2017). This unique developmental timeline of the breast results in increased susceptibility to carcinogens during the proliferative phases followed by a long-term decrease in susceptibility after early pregnancy and later in life. This theory underlies the current efforts to prevent breast cancers by induction of terminal differentiation (mimicking pregnancy) in teenagers (Santucci-Pereira, George et al. 2013).

Estrogen

The modification of breast cancer risk from IR with age is likely related to the age and parity-dependent changes in hormones and their effects on the proliferation and differentiation of epithelial cells in the breast. As with spontaneous breast cancer, hormones increase the risk of breast cancer following ionizing radiation in women. Breast cancer rates following exposure to therapeutic doses of radiation (for cancers including Hodgkin’s lymphoma) are lower in women who subsequently undergo premature menopause or whose treatment involved higher doses of radiation to the ovaries causing effects similar to early menopause (Travis, Hill et al. 2003; De Bruin, Sparidans et al. 2009; Inskip, Robison et al. 2009; Moskowitz, Chou et al. 2014). Genetic variation in estrogen signaling also affects risk. Polymorphisms in estrogen synthesis and metabolism genes modify the risk of breast cancer after occupational or diagnostic exposure to X-rays (Sigurdson, Bhatti et al. 2009). Similarly, risk increases with and may be partially mediated by increased serum estrogen in postmenopausal atomic bomb survivors (Grant, Cologne et al. 2018).

Similarly, exposure to estrogen or the synthetic estrogen diethylstilbestrol (DES) is associated with more tumors (particularly adenocarcinomas) in rats following IR. This effect can be observed in intact rats supplemented with DES or estradiol (E2) before, concurrent with or after IR (Segaloff and Maxfield 1971; Shellabarger, Stone et al. 1976; Holtzman, Stone et al. 1979; Holtzman, Stone et al. 1981; Solleveld, van Zwieten et al. 1986; Broerse, Hennen et al. 1987; Inano, Suzuki et al. 1991). This increased effect of radiation in the presence of estrogen can also be observed in male rats treated with DES (Inano, Suzuki et al. 1996) and ovariectomized rats (OVX) treated before or after puberty with estradiol (Inano, Yamanouchi et al. 1995; Yamanouchi, Ishii-Ohba et al. 1995). Conversely, OVX (Cronkite, Shellabarger et al. 1960; Clifton, Yasukawa-Barnes et al. 1985; Solleveld, van Zwieten et al. 1986) and the anti-estrogen tamoxifen (Welsch, Goodrich-Smith et al. 1981; Lemon, Kumar et al. 1989; Peterson, Servinsky et al. 2005) reduce tumors from IR. In addition, one study reports that IR can increase circulating estrogen in rodents (Suman, Johnson et al. 2012). While this effect would be consistent with reports in postmenopausal women after the atomic bomb, the finding has not been repeated.

The effect of progesterone on carcinogenesis depends on the developmental state of the mammary gland. Progesterone does not appear to have a strong effect in pre-pubertal or immature mammary gland, which has not proliferated in response to estrogen (Inano, Yamanouchi et al. 1995). In contrast, progesterone was associated with elevated risk of carcinogenesis after IR in post-pubertal rats (Yamanouchi, Ishii-Ohba et al. 1995; Takabatake, Daino et al. 2018), consistent with a combined effect of estrogen and progesterone on breast cancer risk seen in the Women’s Health Initiative trials (Chlebowski, Aragaki et al. 2015). Curiously, in some studies progesterone reduces the effect of E2 on IR-induced tumorigenesis (Inano, Yamanouchi et al. 1995; Yamanouchi, Ishii-Ohba et al. 1995). In this case the combined E2 and progesterone treatment may have actually matured the breast in a manner akin to pregnancy – estrogen levels were higher than typical for pregnancy and lactation in rats and the resulting glands were highly developed and had no terminal end buds (Inano, Yamanouchi et al. 1995; Yamanouchi, Ishii-Ohba et al. 1995).

Several studies suggest that therapeutic (Huang, Newman et al. 2000; Castiglioni, Terenziani et al. 2007; Dores, Anderson et al. 2010; Neta, Anderson et al. 2012; Horst, Hancock et al. 2014; Alkner, Ehinger et al. 2015) and environmental (VoPham, DuPre et al. 2017) ionizing radiation particularly increase the risk of estrogen receptor negative (ER-) breast tumors in women, possibly by acting on ER- stem cells in the breast. It should be noted, however, that most of these studies are in women with a history of prior cancer. On the other hand, in a study of low dose diagnostic radiation exposure and another small study of atomic exposed women there was no association between exposure and tumors’ estrogen receptor status (Ma, Hill et al. 2008; Miura, Nakashima et al. 2008).

In animals, tumors formed after IR in the absence of estrogen (ovariectomized animals) are often ER- while those formed in the presence of estrogen or DES are often ER+ (Inano, Yamanouchi et al. 1995) and those formed in the presence of estrogen and progesterone are almost always ER+ (Inano, Yamanouchi et al. 1995; Yamanouchi, Ishii-Ohba et al. 1995).

Genetic susceptibility

Susceptibility to breast cancer from ionizing radiation varies with genetic background. Women with certain genetic polymorphisms in DNA damage response genes such as BRCA or ATM are more susceptible to breast cancer from ionizing radiation (Millikan, Player et al. 2005; Broeks, Braaf et al. 2007; Brooks, Teraoka et al. 2012; Bernstein, Thomas et al. 2013), particularly when exposed at a younger age (Andrieu, Easton et al. 2006; Broeks, Braaf et al. 2007; Bernstein, Haile et al. 2010; Pijpe, Andrieu et al. 2012). Polymorphisms in estrogen synthesis and metabolism also affect risk of breast cancer from IR (Sigurdson, Bhatti et al. 2009). An early study of women exposed to the atomic bomb also suggested that a surge in rapid onset cancers arose from genetically susceptible populations (Land, Tokunaga et al. 1993).

In rodents, certain strains (genetically different families of a species) are more susceptible to mammary cancer following ionizing radiation than others, indicating genetic influences on susceptibility (Shellabarger 1972; Vogel and Turner 1982; Imaoka, Nishimura et al. 2007; Rivina, Davoren et al. 2016).

Dose dependence

Breast cancer risk increases linearly across a wide range of ionizing radiation doses in humans (Miller, Howe et al. 1989; Boice, Preston et al. 1991; Preston, Mattsson et al. 2002; Preston, Ron et al. 2007; Ronckers, Doody et al. 2008; Inskip, Robison et al. 2009; Adams, Dozier et al. 2010; Eidemuller, Holmberg et al. 2015; Little and McElvenny 2017; Shore, Beck et al. 2018) and in animals (Gragtmans, Myers et al. 1984; Imaoka, Nishimura et al. 2007), although some flattening may occur at the highest doses (attributed to cell killing effects) (Imaoka, Nishimura et al. 2007; Ibrahim, Abouelkhair et al. 2012; Moskowitz, Chou et al. 2014). Cancer data at doses lower than 0.1-0.2 Gy is scarce and conflicting, with some studies showing significant increases in cancers among individuals exposed to lower doses compared with unexposed people (Preston, Mattsson et al. 2002; Sigurdson, Bhatti et al. 2009; Adams, Dozier et al. 2010), including among genetically susceptible BRCA carriers (Pijpe, Andrieu et al. 2012), while others have not (Jacrot, Mouriquand et al. 1979; Imaoka, Nishimura et al. 2007; Sasaki, Tachibana et al. 2014). While gamma radiation elicits a linear low-dose response, mammary tumor risk after higher LET radiation exhibited steeper dose-dependence at lower doses (Imaoka, Nishimura et al. 2007). Despite the higher uncertainty around individual breast cancer studies after low doses of IR, a recent review of the dose-response of solid tumors IR including several focused on breast cancer concluded that the evidence supported a linear no-threshold dose response model even at lower doses (Shore, Beck et al. 2018).

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Boice, J. D., Jr., D. Preston, et al. (1991). "Frequent chest X-ray fluoroscopy and breast cancer incidence among tuberculosis patients in Massachusetts." Radiation research 125(2): 214-222.

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Broeks, A., L. M. Braaf, et al. (2007). "Identification of women with an increased risk of developing radiation-induced breast cancer: a case only study." Breast cancer research : BCR 9(2): R26.

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Chlebowski, R. T., A. K. Aragaki, et al. (2015). "Menopausal Hormone Therapy Influence on Breast Cancer Outcomes in the Women's Health Initiative." J Natl Compr Canc Netw 13(7): 917-924.

Clifton, K. H., J. Yasukawa-Barnes, et al. (1985). "Irradiation and prolactin effects on rat mammary carcinogenesis: intrasplenic pituitary and estrone capsule implants." Journal of the National Cancer Institute 75(1): 167-175.

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De Bruin, M. L., J. Sparidans, et al. (2009). "Breast cancer risk in female survivors of Hodgkin's lymphoma: lower risk after smaller radiation volumes." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 27(26): 4239-4246.

Dores, G. M., W. F. Anderson, et al. (2010). "Risk of breast cancer according to clinicopathologic features among long-term survivors of Hodgkin's lymphoma treated with radiotherapy." British journal of cancer 103(7): 1081-1084.

Eidemuller, M., E. Holmberg, et al. (2015). "Breast cancer risk and possible mechanisms of radiation-induced genomic instability in the Swedish hemangioma cohort after reanalyzed dosimetry." Mutation research 775: 1-9.

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Grant, E. J., J. B. Cologne, et al. (2018). "Bioavailable serum estradiol may alter radiation risk of postmenopausal breast cancer: a nested case-control study." International journal of radiation biology 94(2): 97-105.

Henderson, T. O., A. Amsterdam, et al. (2010). "Systematic review: surveillance for breast cancer in women treated with chest radiation for childhood, adolescent, or young adult cancer." Annals of internal medicine 152(7): 444-455.

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Holtzman, S., J. P. Stone, et al. (1979). "Synergism of diethylstilbestrol and radiation in mammary carcinogenesis in female F344 rats." Journal of the National Cancer Institute 63(4): 1071-1074.

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Holtzman, S., J. P. Stone, et al. (1982). "Radiation-induced mammary carcinogenesis in virgin, pregnant, lactating, and postlactating rats." Cancer Res 42(1): 50-53.

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Imaoka, T., M. Nishimura, et al. (2017). "Age Modifies the Effect of 2-MeV Fast Neutrons on Rat Mammary Carcinogenesis." Radiation research 188(4): 419-425.

Imaoka, T., M. Nishimura, et al. (2013). "Influence of age on the relative biological effectiveness of carbon ion radiation for induction of rat mammary carcinoma." International journal of radiation oncology, biology, physics 85(4): 1134-1140.

Imaoka, T., M. Nishimura, et al. (2009). "Radiation-induced mammary carcinogenesis in rodent models: what's different from chemical carcinogenesis?" J Radiat Res 50(4): 281-293.

Imaoka, T., M. Nishimura, et al. (2011). "Pre- and postpubertal irradiation induces mammary cancers with distinct expression of hormone receptors, ErbB ligands, and developmental genes in rats." Mol Carcinog 50(7): 539-552.

Imaoka, T., M. Nishimura, et al. (2007). "High relative biologic effectiveness of carbon ion radiation on induction of rat mammary carcinoma and its lack of H-ras and Tp53 mutations." International journal of radiation oncology, biology, physics 69(1): 194-203.

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Inano, H., K. Suzuki, et al. (1996). "Relationship between induction of mammary tumors and change of testicular functions in male rats following gamma-ray irradiation and/or diethylstilbestrol." Carcinogenesis 17(2): 355-360.

Inano, H., K. Suzuki, et al. (1996). "Susceptibility of fetal, virgin, pregnant and lactating rats for the induction of mammary tumors by gamma rays." Radiation research 145(6): 708-713.

Inano, H., H. Yamanouchi, et al. (1995). "Estradiol-17 beta as an initiation modifier for radiation-induced mammary tumorigenesis of rats ovariectomized before puberty." Carcinogenesis 16(8): 1871-1877.

Inskip, P. D., L. L. Robison, et al. (2009). "Radiation dose and breast cancer risk in the childhood cancer survivor study." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 27(24): 3901-3907.

Jacrot, M., J. Mouriquand, et al. (1979). "Mammary carcinogenesis in Sprague--Dawley rats following 3 repeated exposures to 14.8 MeV neutrons and steroid receptor content of these tumor types." Cancer Lett 8(2): 147-153.

Land, C. E., N. Hayakawa, et al. (1994). "A case-control interview study of breast cancer among Japanese A-bomb survivors. II. Interactions with radiation dose." Cancer Causes Control 5(2): 167-176.

Land, C. E., M. Tokunaga, et al. (2003). "Incidence of female breast cancer among atomic bomb survivors, Hiroshima and Nagasaki, 1950-1990." Radiation research 160(6): 707-717.

Land, C. E., M. Tokunaga, et al. (1993). "Early-onset breast cancer in A-bomb survivors." Lancet 342(8865): 237.

Lemon, H. M., P. F. Kumar, et al. (1989). "Inhibition of radiogenic mammary carcinoma in rats by estriol or tamoxifen." Cancer 63(9): 1685-1692.

Little, M. P. and D. M. McElvenny (2017). "Male Breast Cancer Incidence and Mortality Risk in the Japanese Atomic Bomb Survivors - Differences in Excess Relative and Absolute Risk from Female Breast Cancer." Environmental health perspectives 125(2): 223-229.

Ma, H., K. D. Henderson, et al. (2010). "Pregnancy-related factors and the risk of breast carcinoma in situ and invasive breast cancer among postmenopausal women in the California Teachers Study cohort." Breast cancer research : BCR 12(3): R35.

Ma, H., C. K. Hill, et al. (2008). "Low-dose medical radiation exposure and breast cancer risk in women under age 50 years overall and by estrogen and progesterone receptor status: results from a case-control and a case-case comparison." Breast cancer research and treatment 109(1): 77-90.

McDaniel, S. M., K. K. Rumer, et al. (2006). "Remodeling of the mammary microenvironment after lactation promotes breast tumor cell metastasis." Am J Pathol 168(2): 608-620.

Miller, A. B., G. R. Howe, et al. (1989). "Mortality from breast cancer after irradiation during fluoroscopic examinations in patients being treated for tuberculosis." The New England journal of medicine 321(19): 1285-1289.

Millikan, R. C., J. S. Player, et al. (2005). "Polymorphisms in DNA repair genes, medical exposure to ionizing radiation, and breast cancer risk." Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 14(10): 2326-2334.

Miura, S., M. Nakashima, et al. (2008). "Significance of HER2 and C-MYC oncogene amplifications in breast cancer in atomic bomb survivors: associations with radiation exposure and histologic grade." Cancer 112(10): 2143-2151.

Moskowitz, C. S., J. F. Chou, et al. (2014). "Breast cancer after chest radiation therapy for childhood cancer." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 32(21): 2217-2223.

Neta, G., W. F. Anderson, et al. (2012). "Variation in the risk of radiation-related contralateral breast cancer by histology and estrogen receptor expression in SEER." Breast cancer research and treatment 131(3): 1021-1027.

Oakes, S. R., H. N. Hilton, et al. (2006). "The alveolar switch: coordinating the proliferative cues and cell fate decisions that drive the formation of lobuloalveoli from ductal epithelium." Breast cancer research : BCR 8(2): 207.

Ozasa, K., Y. Shimizu, et al. (2012). "Studies of the mortality of atomic bomb survivors, Report 14, 1950-2003: an overview of cancer and noncancer diseases." Radiation research 177(3): 229-243.

Peterson, N. C., M. D. Servinsky, et al. (2005). "Tamoxifen resistance and Her2/neu expression in an aged, irradiated rat breast carcinoma model." Carcinogenesis 26(9): 1542-1552.

Pijpe, A., N. Andrieu, et al. (2012). "Exposure to diagnostic radiation and risk of breast cancer among carriers of BRCA1/2 mutations: retrospective cohort study (GENE-RAD-RISK)." BMJ 345: e5660.

Preston, D. L., A. Mattsson, et al. (2002). "Radiation effects on breast cancer risk: a pooled analysis of eight cohorts." Radiation research 158(2): 220-235.

Preston, D. L., E. Ron, et al. (2007). "Solid cancer incidence in atomic bomb survivors: 1958-1998." Radiation research 168(1): 1-64.

Rajkumar, L., F. S. Kittrell, et al. (2007). "Hormone-induced protection of mammary tumorigenesis in genetically engineered mouse models." Breast cancer research : BCR 9(1): R12.

Rivina, L., M. J. Davoren, et al. (2016). "Mouse models for radiation-induced cancers." Mutagenesis 31(5): 491-509.

Ronckers, C. M., M. M. Doody, et al. (2008). "Multiple diagnostic X-rays for spine deformities and risk of breast cancer." Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 17(3): 605-613.

Russo, J. (2015). "Significance of rat mammary tumors for human risk assessment." Toxicologic pathology 43(2): 145-170.

Santucci-Pereira, J., C. George, et al. (2013). "Mimicking pregnancy as a strategy for breast cancer prevention." Breast Cancer Manag 2(4): 283-294.

Sasaki, M. S., A. Tachibana, et al. (2014). "Cancer risk at low doses of ionizing radiation: artificial neural networks inference from atomic bomb survivors." J Radiat Res 55(3): 391-406.

Segaloff, A. and W. S. Maxfield (1971). "The synergism between radiation and estrogen in the production of mammary cancer in the rat." Cancer Res 31(2): 166-168.

Shellabarger, C. J. (1972). "Mammary neoplastic response of Lewis and Sprague-Dawley female rats to 7,12-dimethylbenz(a)anthracene or x-ray." Cancer research 32(5): 883-885.

Shellabarger, C. J., J. P. Stone, et al. (1976). "Synergism between neutron radiation and diethylstilbestrol in the production of mammary adenocarcinomas in the rat." Cancer research 36(3): 1019-1022.

Shore, R. E., H. L. Beck, et al. (2018). "Implications of recent epidemiologic studies for the linear nonthreshold model and radiation protection." J Radiol Prot 38(3): 1217-1233.

Sigurdson, A. J., P. Bhatti, et al. (2009). "Polymorphisms in estrogen biosynthesis and metabolism-related genes, ionizing radiation exposure, and risk of breast cancer among US radiologic technologists." Breast cancer research and treatment 118(1): 177-184.

Solleveld, H. A., M. J. van Zwieten, et al. (1986). "Effects of X-irradiation, ovariohysterectomy and estradiol-17 beta on incidence, benign/malignant ratio and multiplicity of rat mammary neoplasms--a preliminary report." Leuk Res 10(7): 755-759.

Sternlicht, M. D., S. W. Sunnarborg, et al. (2005). "Mammary ductal morphogenesis requires paracrine activation of stromal EGFR via ADAM17-dependent shedding of epithelial amphiregulin." Development 132(17): 3923-3933.

Stovall, M., S. A. Smith, et al. (2008). "Dose to the contralateral breast from radiotherapy and risk of second primary breast cancer in the WECARE study." International journal of radiation oncology, biology, physics 72(4): 1021-1030.

Suman, S., M. D. Johnson, et al. (2012). "Exposure to ionizing radiation causes long-term increase in serum estradiol and activation of PI3K-Akt signaling pathway in mouse mammary gland." International journal of radiation oncology, biology, physics 84(2): 500-507.

Suzuki, K., H. Ishii-Ohba, et al. (1994). "Susceptibility of lactating rat mammary glands to gamma-ray-irradiation-induced tumorigenesis." Int J Cancer 56(3): 413-417.

Takabatake, M., K. Daino, et al. (2018). "Differential effect of parity on rat mammary carcinogenesis after pre- or post-pubertal exposure to radiation." Sci Rep 8(1): 14325.

Travis, L. B., D. A. Hill, et al. (2003). "Breast cancer following radiotherapy and chemotherapy among young women with Hodgkin disease." JAMA 290(4): 465-475.

Vogel, H. H., Jr. and J. E. Turner (1982). "Genetic component in rat mammary carcinogenesis." Radiation research 89(2): 264-273.

VoPham, T., N. DuPre, et al. (2017). "Environmental radon exposure and breast cancer risk in the Nurses' Health Study II." Environmental health : a global access science source 16(1): 97.

Wagner, K. U. (2004). "Models of breast cancer: quo vadis, animal modeling?" Breast cancer research : BCR 6(1): 31-38.

Welsch, C. W., M. Goodrich-Smith, et al. (1981). "Effect of an estrogen antagonist (tamoxifen) on the initiation and progression of gamma-irradiation-induced mammary tumors in female Sprague-Dawley rats." European journal of cancer & clinical oncology 17(12): 1255-1258.

Yamanouchi, H., H. Ishii-Ohba, et al. (1995). "Relationship between stages of mammary development and sensitivity to gamma-ray irradiation in mammary tumorigenesis in rats." Int J Cancer 60(2): 230-234

Increased reactive oxygen and nitrogen species (RONS) leading to increased risk of breast cancer

Human

Rodent

Modifying factors

Age

Estrogen

Genetic susceptibility

Dose dependence

Bartstra, R. W., P. A. Bentvelzen, et al. (1998). "Induction of mammary tumors in rats by single-dose gamma irradiation at different ages." Radiation research 150(4): 442-450.

Berrington de Gonzalez, A., R. E. Curtis, et al. (2010). "Second solid cancers after radiotherapy for breast cancer in SEER cancer registries." British journal of cancer 102(1): 220-226.

Bijwaard, H., A. Brenner, et al. (2010). "Breast cancer risk from different mammography screening practices." Radiation research 174(3): 367-376.

Boice, J. D., Jr., D. Preston, et al. (1991). "Frequent chest X-ray fluoroscopy and breast cancer incidence among tuberculosis patients in Massachusetts." Radiation research 125(2): 214-222.

Britt, K., A. Ashworth, et al. (2007). "Pregnancy and the risk of breast cancer." Endocrine-related cancer 14(4): 907-933.

Broeks, A., L. M. Braaf, et al. (2007). "Identification of women with an increased risk of developing radiation-induced breast cancer: a case only study." Breast cancer research : BCR 9(2): R26.

Castiglioni, F., M. Terenziani, et al. (2007). "Radiation effects on development of HER2-positive breast carcinomas." Clin Cancer Res 13(1): 46-51.

Chlebowski, R. T., A. K. Aragaki, et al. (2015). "Menopausal Hormone Therapy Influence on Breast Cancer Outcomes in the Women's Health Initiative." J Natl Compr Canc Netw 13(7): 917-924.

Dall, G., G. Risbridger, et al. (2017). "Mammary stem cells and parity-induced breast cancer protection- new insights." The Journal of steroid biochemistry and molecular biology 170: 54-60.

Gragtmans, N. J., D. K. Myers, et al. (1984). "Occurrence of mammary tumors in rats after exposure to tritium beta rays and 200-kVp X rays." Radiation research 99(3): 636-650.

Hinck, L. and G. B. Silberstein (2005). "Key stages in mammary gland development: the mammary end bud as a motile organ." Breast cancer research : BCR 7(6): 245-251.

Holtzman, S., J. P. Stone, et al. (1979). "Synergism of diethylstilbestrol and radiation in mammary carcinogenesis in female F344 rats." Journal of the National Cancer Institute 63(4): 1071-1074.

Holtzman, S., J. P. Stone, et al. (1981). "Synergism of estrogens and X-rays in mammary carcinogenesis in female ACI rats." Journal of the National Cancer Institute 67(2): 455-459.

Holtzman, S., J. P. Stone, et al. (1982). "Radiation-induced mammary carcinogenesis in virgin, pregnant, lactating, and postlactating rats." Cancer Res 42(1): 50-53.

Horst, K. C., S. L. Hancock, et al. (2014). "Histologic subtypes of breast cancer following radiotherapy for Hodgkin lymphoma." Ann Oncol 25(4): 848-851.

Ibrahim, E. M., K. M. Abouelkhair, et al. (2012). "Risk of second breast cancer in female Hodgkin's lymphoma survivors: a meta-analysis." BMC Cancer 12: 197.

Imaoka, T., M. Nishimura, et al. (2017). "Age Modifies the Effect of 2-MeV Fast Neutrons on Rat Mammary Carcinogenesis." Radiation research 188(4): 419-425.

Imaoka, T., M. Nishimura, et al. (2009). "Radiation-induced mammary carcinogenesis in rodent models: what's different from chemical carcinogenesis?" J Radiat Res 50(4): 281-293.

Inano, H., K. Suzuki, et al. (1991). "Pregnancy-dependent initiation in tumorigenesis of Wistar rat mammary glands by 60Co-irradiation." Carcinogenesis 12(6): 1085-1090.

Inano, H., K. Suzuki, et al. (1996). "Susceptibility of fetal, virgin, pregnant and lactating rats for the induction of mammary tumors by gamma rays." Radiation research 145(6): 708-713.

Land, C. E., N. Hayakawa, et al. (1994). "A case-control interview study of breast cancer among Japanese A-bomb survivors. II. Interactions with radiation dose." Cancer Causes Control 5(2): 167-176.

Land, C. E., M. Tokunaga, et al. (2003). "Incidence of female breast cancer among atomic bomb survivors, Hiroshima and Nagasaki, 1950-1990." Radiation research 160(6): 707-717.

Land, C. E., M. Tokunaga, et al. (1993). "Early-onset breast cancer in A-bomb survivors." Lancet 342(8865): 237.

Lemon, H. M., P. F. Kumar, et al. (1989). "Inhibition of radiogenic mammary carcinoma in rats by estriol or tamoxifen." Cancer 63(9): 1685-1692.

McDaniel, S. M., K. K. Rumer, et al. (2006). "Remodeling of the mammary microenvironment after lactation promotes breast tumor cell metastasis." Am J Pathol 168(2): 608-620.

Ozasa, K., Y. Shimizu, et al. (2012). "Studies of the mortality of atomic bomb survivors, Report 14, 1950-2003: an overview of cancer and noncancer diseases." Radiation research 177(3): 229-243.

Peterson, N. C., M. D. Servinsky, et al. (2005). "Tamoxifen resistance and Her2/neu expression in an aged, irradiated rat breast carcinoma model." Carcinogenesis 26(9): 1542-1552.

Pijpe, A., N. Andrieu, et al. (2012). "Exposure to diagnostic radiation and risk of breast cancer among carriers of BRCA1/2 mutations: retrospective cohort study (GENE-RAD-RISK)." BMJ 345: e5660.

Preston, D. L., A. Mattsson, et al. (2002). "Radiation effects on breast cancer risk: a pooled analysis of eight cohorts." Radiation research 158(2): 220-235.

Preston, D. L., E. Ron, et al. (2007). "Solid cancer incidence in atomic bomb survivors: 1958-1998." Radiation research 168(1): 1-64.

Rajkumar, L., F. S. Kittrell, et al. (2007). "Hormone-induced protection of mammary tumorigenesis in genetically engineered mouse models." Breast cancer research : BCR 9(1): R12.

Rivina, L., M. J. Davoren, et al. (2016). "Mouse models for radiation-induced cancers." Mutagenesis 31(5): 491-509.

Russo, J. (2015). "Significance of rat mammary tumors for human risk assessment." Toxicologic pathology 43(2): 145-170.

Santucci-Pereira, J., C. George, et al. (2013). "Mimicking pregnancy as a strategy for breast cancer prevention." Breast Cancer Manag 2(4): 283-294.

Sasaki, M. S., A. Tachibana, et al. (2014). "Cancer risk at low doses of ionizing radiation: artificial neural networks inference from atomic bomb survivors." J Radiat Res 55(3): 391-406.

Segaloff, A. and W. S. Maxfield (1971). "The synergism between radiation and estrogen in the production of mammary cancer in the rat." Cancer Res 31(2): 166-168.

Shellabarger, C. J. (1972). "Mammary neoplastic response of Lewis and Sprague-Dawley female rats to 7,12-dimethylbenz(a)anthracene or x-ray." Cancer research 32(5): 883-885.

Shore, R. E., H. L. Beck, et al. (2018). "Implications of recent epidemiologic studies for the linear nonthreshold model and radiation protection." J Radiol Prot 38(3): 1217-1233.

Suzuki, K., H. Ishii-Ohba, et al. (1994). "Susceptibility of lactating rat mammary glands to gamma-ray-irradiation-induced tumorigenesis." Int J Cancer 56(3): 413-417.

Takabatake, M., K. Daino, et al. (2018). "Differential effect of parity on rat mammary carcinogenesis after pre- or post-pubertal exposure to radiation." Sci Rep 8(1): 14325.

Travis, L. B., D. A. Hill, et al. (2003). "Breast cancer following radiotherapy and chemotherapy among young women with Hodgkin disease." JAMA 290(4): 465-475.

Vogel, H. H., Jr. and J. E. Turner (1982). "Genetic component in rat mammary carcinogenesis." Radiation research 89(2): 264-273.

VoPham, T., N. DuPre, et al. (2017). "Environmental radon exposure and breast cancer risk in the Nurses' Health Study II." Environmental health : a global access science source 16(1): 97.

Wagner, K. U. (2004). "Models of breast cancer: quo vadis, animal modeling?" Breast cancer research : BCR 6(1): 31-38.

Oxidative DNA damage leading to chromosomal aberrations and mutations

There is no evidence text for this AOP

Direct deposition of ionizing energy leading to lung cancer

There is no evidence text for this AOP

Chronic reactive oxygen species leading to human treatment-resistant gastric cancer

There is no evidence text for this AOP

Event Evidence

This table is automatically generated and includes the Events with this associated stressor as well as the evidence text from this Event Stressor. More help

Increase in reactive oxygen and nitrogen species (RONS)

Reactive oxygen and nitrogen species are created by the interaction of ionizing radiation with tissue. When ionizing radiation encounters water or extracellular or intracellular components, it releases energy. This energy ejects electrons from atoms and molecules, and the ejected electrons pass energy on to neighboring molecules. Since the majority of biological tissue is composed of water molecules, ionizing radiation results in the radiolysis of water to hydroxyl radicals, which can interact to form additional reactive molecules. This reaction is generally accepted. Because RONS have such a short half-life, their appearance has been historically measured by their effect on the cell (e.g. in terms of DNA damage), and only more recently characterized using molecular probes that directly reflect their occurrence.

The time course of RONS following ionizing radiation has been described using molecular probes- primarily the non-specific fluorescent probe for ROS DCHF as well as non-specific lipid peroxidation. ROS levels increase at multiple time points: in vitro immediately following radiation (Denissova, Nasello et al. 2012; Yoshida, Goto et al. 2012; Martin, Nakamura et al. 2014), around 15 minutes later (Narayanan, Goodwin et al. 1997; Saenko, Cieslar-Pobuda et al. 2013), hours to days (Lyng, Seymour et al. 2001; Yang, Asaad et al. 2005; Choi, Kang et al. 2007; Du, Gao et al. 2009; Das, Manna et al. 2014; Werner, Wang et al. 2014; Ameziane-El-Hassani, Talbot et al. 2015; Manna, Das et al. 2015; Zhang, Zhu et al. 2017), and in vivo intestinal epithelial cells and bone marrow stem cells showed elevated ROS up to a year after IR exposure of the animal (Pazhanisamy, Li et al. 2011; Datta, Suman et al. 2012). In intestinal epithelial cells, widespread ROS expression over a period of weeks would require transgenerational expression of ROS, indicating that a cell with increased RONS can pass that characteristic to its daughter cells.

Multiple mechanisms underlie the increase in RONS after IR. The early (15 minute) and later (days to weeks) elevation in ROS is associated with increased NADPH-oxidase production of superoxide and H2O2 (Narayanan, Goodwin et al. 1997; Ameziane-El-Hassani, Talbot et al. 2015), and intermediate (hours to days) and chronic ROS elevation has been associated with mitochondrial respiration (Dayal, Martin et al. 2009; Datta, Suman et al. 2012; Saenko, Cieslar-Pobuda et al. 2013). The increase in mitochondrial respiration may be supported by nitric oxide, which increases around 8 hours after IR and remains elevated through at least day 2. A chronic (1 year) ROS effect of IR was not observed in cell culture when cell divisions were limited, potentially implicating cell division in sustaining chronic RONS (Suzuki, Kashino et al. 2009). RONS can also be indirectly initiated by ionizing radiation in neighboring cells via unknown soluble factors, possibly including extracellular H2O2, which is elevated immediately and in the first week following IR (Driessens, Versteyhe et al. 2009; Ameziane-El-Hassani, Boufraqech et al. 2010; Ameziane-El-Hassani, Talbot et al. 2015). Elevated intracellular ROS was observed in cells after exposure to media from IR-exposed cells (Narayanan, Goodwin et al. 1997; Lyng, Seymour et al. 2001; Yang, Asaad et al. 2005), and protein carbonylation and lipid oxidation reflecting RONS activity was elevated in cells 20 passages after exposure to media from IR cells (Buonanno, de Toledo et al. 2011), suggesting that the effect of IR on RONS can penetrate well beyond the directly exposed cells in both space and time.

Few studies have measured RONS at multiple doses of ionizing radiation, and the time points, doses, and cell types tested for dose response vary between studies along with the dose-dependence. Two studies report dose-dependence of RONS measured with lipid peroxidation or DCHF in response to a few doses between 0.5 and 12 Gy IR (Jones, Riggs et al. 2007; Saenko, Cieslar-Pobuda et al. 2013), dose-dependence of ROS only at lower doses below 1 Gy (Werner, Wang et al. 2014), or non-linear dose-dependence (Narayanan, Goodwin et al. 1997). Dose-dependent RONS responses are also reported in extracellular media (Driessens, Versteyhe et al. 2009), and in bystander cells not directly exposed to IR (Narayanan, Goodwin et al. 1997), even after multiple generations in culture (Buonanno, de Toledo et al. 2011). ROS appears to be more dose-dependent immediately after IR and after 24 hours following IR with less dose-dependence at times in between (Narayanan, Goodwin et al. 1997; Saenko, Cieslar-Pobuda et al. 2013; Zhang, Zhu et al. 2017), possibly reflecting different mechanisms of ROS generation. These studies use probes for ROS or indicators of oxidation, but none that we are aware of explicitly measures indicators of RNS at different doses of IR.

Ameziane-El-Hassani, R., M. Boufraqech, et al. (2010). "Role of H2O2 in RET/PTC1 chromosomal rearrangement produced by ionizing radiation in human thyroid cells." Cancer Res 70(10): 4123-4132.

Ameziane-El-Hassani, R., M. Talbot, et al. (2015). "NADPH oxidase DUOX1 promotes long-term persistence of oxidative stress after an exposure to irradiation." Proceedings of the National Academy of Sciences of the United States of America 112(16): 5051-5056.

Buonanno, M., S. M. de Toledo, et al. (2011). "Long-term consequences of radiation-induced bystander effects depend on radiation quality and dose and correlate with oxidative stress." Radiation research 175(4): 405-415.

Choi, K. M., C. M. Kang, et al. (2007). "Ionizing radiation-induced micronucleus formation is mediated by reactive oxygen species that are produced in a manner dependent on mitochondria, Nox1, and JNK." Oncol Rep 17(5): 1183-1188.

Das, U., K. Manna, et al. (2014). "Role of ferulic acid in the amelioration of ionizing radiation induced inflammation: a murine model." PLoS One 9(5): e97599.

Datta, K., S. Suman, et al. (2012). "Exposure to heavy ion radiation induces persistent oxidative stress in mouse intestine." PLoS One 7(8): e42224.

Dayal, D., S. M. Martin, et al. (2009). "Mitochondrial complex II dysfunction can contribute significantly to genomic instability after exposure to ionizing radiation." Radiation research 172(6): 737-745.

Denissova, N. G., C. M. Nasello, et al. (2012). "Resveratrol protects mouse embryonic stem cells from ionizing radiation by accelerating recovery from DNA strand breakage." Carcinogenesis 33(1): 149-155.

Driessens, N., S. Versteyhe, et al. (2009). "Hydrogen peroxide induces DNA single- and double-strand breaks in thyroid cells and is therefore a potential mutagen for this organ." Endocrine-related cancer 16(3): 845-856.

Du, C., Z. Gao, et al. (2009). "Mitochondrial ROS and radiation induced transformation in mouse embryonic fibroblasts." Cancer Biol Ther 8(20): 1962-1971.

Jones, J. A., P. K. Riggs, et al. (2007). "Ionizing radiation-induced bioeffects in space and strategies to reduce cellular injury and carcinogenesis." Aviat Space Environ Med 78(4 Suppl): A67-78.

Lyng, F. M., C. B. Seymour, et al. (2001). "Oxidative stress in cells exposed to low levels of ionizing radiation." Biochemical Society transactions 29(Pt 2): 350-353.

Manna, K., U. Das, et al. (2015). "Naringin inhibits gamma radiation-induced oxidative DNA damage and inflammation, by modulating p53 and NF-kappaB signaling pathways in murine splenocytes." Free Radic Res 49(4): 422-439.

Martin, N. T., K. Nakamura, et al. (2014). "Homozygous mutation of MTPAP causes cellular radiosensitivity and persistent DNA double-strand breaks." Cell Death Dis 5: e1130.

Narayanan, P. K., E. H. Goodwin, et al. (1997). "Alpha particles initiate biological production of superoxide anions and hydrogen peroxide in human cells." Cancer research 57(18): 3963-3971.

Pazhanisamy, S. K., H. Li, et al. (2011). "NADPH oxidase inhibition attenuates total body irradiation-induced haematopoietic genomic instability." Mutagenesis 26(3): 431-435.

Saenko, Y., A. Cieslar-Pobuda, et al. (2013). "Changes of reactive oxygen and nitrogen species and mitochondrial functioning in human K562 and HL60 cells exposed to ionizing radiation." Radiation research 180(4): 360-366.

Suzuki, K., G. Kashino, et al. (2009). "Long-term persistence of X-ray-induced genomic instability in quiescent normal human diploid cells." Mutation research 671(1-2): 33-39.

Werner, E., H. Wang, et al. (2014). "Opposite roles for p38MAPK-driven responses and reactive oxygen species in the persistence and resolution of radiation-induced genomic instability." PLoS One 9(10): e108234.

Yang, H., N. Asaad, et al. (2005). "Medium-mediated intercellular communication is involved in bystander responses of X-ray-irradiated normal human fibroblasts." Oncogene 24(12): 2096-2103.

Yoshida, T., S. Goto, et al. (2012). "Mitochondrial dysfunction, a probable cause of persistent oxidative stress after exposure to ionizing radiation." Free Radic Res 46(2): 147-153.

Zhang, Q., L. Zhu, et al. (2017). "Ionizing radiation promotes CCL27 secretion from keratinocytes through the cross talk between TNF-alpha and ROS." J Biochem Mol Toxicol 31(3)

Increase, DNA damage

When ionizing radiation enters a cell and interacts with cellular components including double stranded DNA, it releases energy that leads to DNA damage. This energy ejects electrons from atoms and molecules, and these electrons can produce more electrons, directly ionize DNA, or radiolyze water to form hydroxyl molecules which damage DNA (Hutchinson 1985; Ward 1988; Ravanat, Breton et al. 2014). DNA damage observed after IR includes oxidized base, sugar (deoxyribose), and phosphate lesions, single and double strand breaks, and cross-linking (Ward 1988; Roots, Holley et al. 1990; Haegele, Wolfe et al. 1998; Pouget, Frelon et al. 2002; Rothkamm and Lobrich 2003). DNA damage from IR can occur in a clustered pattern, even from a single particle or photon (Sutherland, Bennett et al. 2002). The type and amount of DNA damage depends on both the quality and dose of radiation. Higher LET radiation such as alpha particles generates more complex clusters of damage including more frequent double strand breaks (Ottolenghi, Merzagora et al. 1997; Rydberg, Heilbronn et al. 2002; Watanabe, Rahmanian et al. 2015; Nikitaki, Nikolov et al. 2016) and other chromosomal abnormalities (Yang, Georgy et al. 1997; Anderson, Stevens et al. 2002), while lower LET radiation (gamma rays, X-rays) generates more oxidized base damage and single strand breaks (Douki, Ravanat et al. 2006).

Damage is also observed in DNA in cells not directly in the path of ionizing radiation, or at a delay following exposure. Indirect or bystander effects are mediated by multiple factors including RONS (Yang, Asaad et al. 2005), TGF-β (Dickey, Baird et al. 2009), and other cytokines (Havaki, Kotsinas et al. 2015). DNA damage following ionizing radiation in directly and indirectly damaged cells is repaired over the first few hours or days (Nikitaki, Nikolov et al. 2016), but long term DNA damage can reoccur as genomic instability weeks, months, or even years after the initial exposure and persist in subsequent generations of cells in vivo (Pazhanisamy, Li et al. 2011; Datta, Suman et al. 2012; Mukherjee, Coates et al. 2012; Snijders, Marchetti et al. 2012) and in vitro (Moore, Marsden et al. 2005; Natarajan, Gibbons et al. 2007; Buonanno, de Toledo et al. 2011; Bensimon, Biard et al. 2016).

Double strand breaks occur linearly with dose between 0.001 Gy (the lowest dose at which an effect has been reliably observed) to over 80 Gy in irradiated cells (Rydberg, Heilbronn et al. 2002; Rothkamm and Lobrich 2003; Yang, Asaad et al. 2005; Asaithamby and Chen 2009). Some low dose studies find a steeper slope between 0.001 and 0.01 Gy for X-rays (although not gamma rays), possibly due to underassessment at higher doses or to a bystander effect superimposed on a linear response (Ojima, Ban et al. 2008; Beels, Werbrouck et al. 2010). Clustered DNA damage also occurs linearly from at least 0.05 Gy (the lowest dose tested) (Sutherland, Bennett et al. 2002), and single strand breaks and alkali sensitive lesions are linear with dose in isolated DNA (Roots, Holley et al. 1990). Chromosomal aberrations appear to be linear or supralinear with dose for low LET radiation (Yang, Georgy et al. 1997; Ryu, Kim et al. 2016) and linear with dose for high LET radiation (Yang, Georgy et al. 1997; Jones, Riggs et al. 2007) at doses examined as low as 0.01 Gy (Schiestl, Khogali et al. 1994; Iwasaki, Takashima et al. 2011). DNA damage measured in bystander cells 1 hour to 3 days after exposure is dose-dependent at low doses (0.001-0.005 Gy), but may approach a maximum between 0.005 and 0.1 Gy (Yang, Anzenberg et al. 2007; Ojima, Ban et al. 2008).

Anderson, R. M., D. L. Stevens, et al. (2002). "M-FISH analysis shows that complex chromosome aberrations induced by alpha -particle tracks are cumulative products of localized rearrangements." Proceedings of the National Academy of Sciences of the United States of America 99(19): 12167-12172.

Asaithamby, A. and D. J. Chen (2009). "Cellular responses to DNA double-strand breaks after low-dose gamma-irradiation." Nucleic acids research 37(12): 3912-3923.

Beels, L., J. Werbrouck, et al. (2010). "Dose response and repair kinetics of gamma-H2AX foci induced by in vitro irradiation of whole blood and T-lymphocytes with X- and gamma-radiation." International journal of radiation biology 86(9): 760-768.

Bensimon, J., D. Biard, et al. (2016). "Forced extinction of CD24 stem-like breast cancer marker alone promotes radiation resistance through the control of oxidative stress." Mol Carcinog 55(3): 245-254.

Datta, K., S. Suman, et al. (2012). "Exposure to heavy ion radiation induces persistent oxidative stress in mouse intestine." PLoS One 7(8): e42224.

Dickey, J. S., B. J. Baird, et al. (2009). "Intercellular communication of cellular stress monitored by gamma-H2AX induction." Carcinogenesis 30(10): 1686-1695.

Douki, T., J. L. Ravanat, et al. (2006). "Minor contribution of direct ionization to DNA base damage inducedby heavy ions." International journal of radiation biology 82(2): 119-127.

Haegele, A. D., P. Wolfe, et al. (1998). "X-radiation induces 8-hydroxy-2'-deoxyguanosine formation in vivo in rat mammary gland DNA." Carcinogenesis 19(7): 1319-1321.

Havaki, S., A. Kotsinas, et al. (2015). "The role of oxidative DNA damage in radiation induced bystander effect." Cancer Lett 356(1): 43-51.

Hutchinson, F. (1985). "Chemical changes induced in DNA by ionizing radiation." Progress in nucleic acid research and molecular biology 32: 115-154.

Iwasaki, T., Y. Takashima, et al. (2011). "The dose response of chromosome aberrations in human lymphocytes induced in vitro by very low-dose gamma rays." Radiation research 175(2): 208-213.

Jones, J. A., P. K. Riggs, et al. (2007). "Ionizing radiation-induced bioeffects in space and strategies to reduce cellular injury and carcinogenesis." Aviat Space Environ Med 78(4 Suppl): A67-78.

Moore, S. R., S. Marsden, et al. (2005). "Genomic instability in human lymphocytes irradiated with individual charged particles: involvement of tumor necrosis factor alpha in irradiated cells but not bystander cells." Radiation research 163(2): 183-190.

Mukherjee, D., P. J. Coates, et al. (2012). "The in vivo expression of radiation-induced chromosomal instability has an inflammatory mechanism." Radiation research 177(1): 18-24.

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.

Nikitaki, Z., V. Nikolov, et al. (2016). "Measurement of complex DNA damage induction and repair in human cellular systems after exposure to ionizing radiations of varying linear energy transfer (LET)." Free radical research 50(sup1): S64-S78.

Ojima, M., N. Ban, et al. (2008). "DNA double-strand breaks induced by very low X-ray doses are largely due to bystander effects." Radiation research 170(3): 365-371.

Ottolenghi, A., M. Merzagora, et al. (1997). "DNA complex lesions induced by protons and alpha-particles: track structure characteristics determining linear energy transfer and particle type dependence." Radiation and environmental biophysics 36(2): 97-103.

Pazhanisamy, S. K., H. Li, et al. (2011). "NADPH oxidase inhibition attenuates total body irradiation-induced haematopoietic genomic instability." Mutagenesis 26(3): 431-435.

Pouget, J. P., S. Frelon, et al. (2002). "Formation of modified DNA bases in cells exposed either to gamma radiation or to high-LET particles." Radiation research 157(5): 589-595.

Ravanat, J. L., J. Breton, et al. (2014). "Radiation-mediated formation of complex damage to DNA: a chemical aspect overview." Br J Radiol 87(1035): 20130715.

Roots, R., W. Holley, et al. (1990). "The formation of strand breaks in DNA after high-LET irradiation: a comparison of data from in vitro and cellular systems." International journal of radiation biology 58(1): 55-69.

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Increase, Cell Proliferation (Epithelial Cells)

While higher doses of ionizing radiation cause cell death in the short term (especially of dividing cells), IR is associated with delayed proliferation in vitro and in vivo. In vitro, IR can promote the proliferation/expansion in p16-suppressed and immortal epithelial populations as well as in bystander CHO cells co-cultured with IR-exposed cells (Han, Chen et al. 2010; Mukhopadhyay, Costes et al. 2010; Tang, Fernandez-Garcia et al. 2014). In vivo, IR increases apoptosis and compensatory proliferation in adult rats (Loree, Koturbash et al. 2006), and long term expression of proliferation in adolescent but not adult mammary gland (Datta, Hyduke et al. 2012; Snijders, Marchetti et al. 2012; Suman, Johnson et al. 2012), possibly via the expansion of a population of stem-like cells in vivo (Nguyen, Oketch-Rabah et al. 2011; Tang, Fernandez-Garcia et al. 2014). This proliferation appears to be associated with TGF-β/Notch activity (Tang, Fernandez-Garcia et al. 2014) and nitric oxide (Han, Chen et al. 2010). IR also increases mammary hyperplasia (Faulkin, Shellabarger et al. 1967; Imaoka, Nishimura et al. 2006). While IR can induce senescence in epithelial cells, IR selects for a post-senescent variant of epithelial cell which would be more conducive to tumorigenesis (Mukhopadhyay, Costes et al. 2010).

Datta, K., D. R. Hyduke, et al. (2012). "Exposure to ionizing radiation induced persistent gene expression changes in mouse mammary gland." Radiat Oncol 7: 205.

Faulkin, J. L. J., C. J. Shellabarger, et al. (1967). "Hyperplastic Lesions of Sprague-Dawley Rat Mammary Glands After X Irradiation2." JNCI: Journal of the National Cancer Institute 39(3): 449-459.

Han, W., S. Chen, et al. (2010). "Nitric oxide mediated DNA double strand breaks induced in proliferating bystander cells after alpha-particle irradiation." Mutation research 684(1-2): 81-89.

Imaoka, T., M. Nishimura, et al. (2006). "Persistent cell proliferation of terminal end buds precedes radiation-induced rat mammary carcinogenesis." In Vivo 20(3): 353-358.

Loree, J., I. Koturbash, et al. (2006). "Radiation-induced molecular changes in rat mammary tissue: possible implications for radiation-induced carcinogenesis." International journal of radiation biology 82(11): 805-815.

Mukhopadhyay, R., S. V. Costes, et al. (2010). "Promotion of variant human mammary epithelial cell outgrowth by ionizing radiation: an agent-based model supported by in vitro studies." Breast cancer research : BCR 12(1): R11.

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.

Tang, J., I. Fernandez-Garcia, et al. (2014). "Irradiation of juvenile, but not adult, mammary gland increases stem cell self-renewal and estrogen receptor negative tumors." Stem Cells 32(3): 649-661.