Stressor: 453
Title
Stressor Overview
AOPs Including This Stressor
| AOP Name | Evidence |
|---|---|
| Increased reactive oxygen and nitrogen species (RONS) leading to increased risk of breast cancer | Moderate |
| Increased DNA damage leading to increased risk of breast cancer | Not Specified |
Events Including This Stressor
Chemical Table
AOP Evidence
Increased reactive oxygen and nitrogen species (RONS) leading to increased risk of breast cancer
Breast carcinogenesis from IR and DNA damaging agents has more similarities than differences (Imaoka, Nishimura et al. 2009). Both IR and other DNA damaging agents form adenocarcinomas in rodents with similar pathology and gene expression, although IR also creates a much larger fraction of fibroadenomas than DNA damaging chemicals (Imaoka, Nishimura et al. 2009). Carcinogenicity for IR and chemical mammary carcinogens NMU and DMBA varies with age and exposure to ovarian hormones (Medina 2007; Imaoka, Nishimura et al. 2009; Russo 2015). Breast carcinogenesis from IR and chemical carcinogens depends strongly on developmental or ongoing exposure to ovarian hormones (Nandi, Guzman et al. 1995; Russo 2015), and estrogen status of tumors increases with ovarian hormone exposure in rats (Nandi, Guzman et al. 1995; Imaoka, Nishimura et al. 2009). The mammary gland is especially susceptible to both IR and mammary carcinogens DMBA and NMU around puberty. This is presumably because puberty is when undifferentiated cells are both large in number and will undergo major subsequent proliferative expansion, although additional factors including metabolism and expression of DNA damage repair genes contribute to variations in the age of maximal susceptibility between agents (Medina 2007; Imaoka, Nishimura et al. 2009; Imaoka, Nishimura et al. 2011; Imaoka, Nishimura et al. 2013). Consistent with general accepted risk assessment assumptions of additivity in carcinogenesis, IR has an additive effect in combination with NMU (Imaoka, Nishimura et al. 2014). Some differences between mammary carcinogens appear around the protective role of breast maturation: pregnancy appears to be more protective in rats exposed to chemical carcinogens than in rats exposed to IR.
The role of DNA damage, mutation, and proliferation outlined in this AOP would presumably apply to other DNA damaging agents while the role of RONS and inflammation is more likely to vary between DNA damaging and other agents based on their ability to induce these key events. DNA damaging agents differ in the degree, type and reparability of the DNA damage they cause. Mammary carcinogens NMU, DMBA, PhIP, and urethane mostly cause adducts with single nucleotide substitutions (Committee to Assess Health Risks from Exposure to Low Levels of Ionizing Radiation 2006; Imaoka, Nishimura et al. 2009; Westcott, Halliwill et al. 2014; Nik-Zainal, Kucab et al. 2015; Sherborne, Davidson et al. 2015). Like ionizing radiation, mammary carcinogen PhIP can cause amplifications and NMU can cause genomic instability (Goepfert, Moreno-Smith et al. 2007; Imaoka, Nishimura et al. 2009). While IR also induces adducts, it characteristically generates complex damage and double-strand breaks leading to deletions and inversions as well as amplification and genomic instability (Pazhanisamy, Li et al. 2011; Datta, Suman et al. 2012; Mukherjee, Coates et al. 2012; Snijders, Marchetti et al. 2012; Yang, Killian et al. 2015; Behjati, Gundem et al. 2016; Mavragani, Nikitaki et al. 2017). The prevalence of complex damage and double strand breaks is likely due to the density of damage delivered by ionizing radiation, but is also attributable to oxidative activity, since IR creates an oxidative state and H2O2 and other oxidizing agents can also cause (less) complex damage, double strand breaks and mutations (Seager, Shah et al. 2012; Sharma, Collins et al. 2016; Cadet, Davies et al. 2017). Radiomimetic compounds (used in chemotherapy) also cause double-strand breaks and simple complex damage. Agents like bleomycin cause double strand breaks through oxidized lesions (Regulus, Duroux et al. 2007), while agents like etoposide and cisplatin cause double strand breaks by interfering with DNA replication forks (Kawashima, Yamaguchi et al. 2017).
Evidence suggests that proliferation and inflammation are also implicated in chemical carcinogenicity. The aforementioned pubertal susceptibility implies a dependence on proliferation, as does the fact that tumorigenesis following NMU depends on proliferation during treatment (Medina 2007). Like IR, NMU and DMBA promote hyperplasia in terminal end buds and ducts and ductal carcinoma in situ leading to carcinogenesis (Goepfert, Moreno-Smith et al. 2007; Medina 2007; Imaoka, Nishimura et al. 2009; Russo 2015). In terms of inflammation, some chemical carcinogens appear to share with IR an increase in inflammatory reactions in mammary stroma and a tumor-promoting effect of stroma (Russo and Russo 1996; Barcellos-Hoff and Ravani 2000; Maffini, Soto et al. 2004; Nguyen, Oketch-Rabah et al. 2011) and although bleomycin has not been characterized for its effects on mammary stroma or mammary carcinogenesis it causes lung fibrosis (an anti-inflammatory reaction) so consistently that it is used as a research model for that endpoint (Moeller, Ask et al. 2008).
Medina, D. (2007). "Chemical carcinogenesis of rat and mouse mammary glands." Breast Dis 28: 63-68.
Increased DNA damage leading to increased risk of breast cancer
Breast carcinogenesis from IR and DNA damaging agents has more similarities than differences (Imaoka, Nishimura et al. 2009). Both IR and other DNA damaging agents form adenocarcinomas in rodents with similar pathology and gene expression, although IR also creates a much larger fraction of fibroadenomas than DNA damaging chemicals (Imaoka, Nishimura et al. 2009). Carcinogenicity for IR and chemical mammary carcinogens NMU and DMBA varies with age and exposure to ovarian hormones (Medina 2007; Imaoka, Nishimura et al. 2009; Russo 2015). Breast carcinogenesis from IR and chemical carcinogens depends strongly on developmental or ongoing exposure to ovarian hormones (Nandi, Guzman et al. 1995; Russo 2015), and estrogen status of tumors increases with ovarian hormone exposure in rats (Nandi, Guzman et al. 1995; Imaoka, Nishimura et al. 2009). The mammary gland is especially susceptible to both IR and mammary carcinogens DMBA and NMU around puberty. This is presumably because puberty is when undifferentiated cells are both large in number and will undergo major subsequent proliferative expansion, although additional factors including metabolism and expression of DNA damage repair genes contribute to variations in the age of maximal susceptibility between agents (Medina 2007; Imaoka, Nishimura et al. 2009; Imaoka, Nishimura et al. 2011; Imaoka, Nishimura et al. 2013). Consistent with general accepted risk assessment assumptions of additivity in carcinogenesis, IR has an additive effect in combination with NMU (Imaoka, Nishimura et al. 2014). Some differences between mammary carcinogens appear around the protective role of breast maturation: pregnancy appears to be more protective in rats exposed to chemical carcinogens than in rats exposed to IR.
The role of DNA damage, mutation, and proliferation outlined in this AOP would presumably apply to other DNA damaging agents while the role of RONS and inflammation is more likely to vary between DNA damaging and other agents based on their ability to induce these key events. DNA damaging agents differ in the degree, type and reparability of the DNA damage they cause. Mammary carcinogens NMU, DMBA, PhIP, and urethane mostly cause adducts with single nucleotide substitutions (Committee to Assess Health Risks from Exposure to Low Levels of Ionizing Radiation 2006; Imaoka, Nishimura et al. 2009; Westcott, Halliwill et al. 2014; Nik-Zainal, Kucab et al. 2015; Sherborne, Davidson et al. 2015). Like ionizing radiation, mammary carcinogen PhIP can cause amplifications and NMU can cause genomic instability (Goepfert, Moreno-Smith et al. 2007; Imaoka, Nishimura et al. 2009). While IR also induces adducts, it characteristically generates complex damage and double-strand breaks leading to deletions and inversions as well as amplification and genomic instability (Pazhanisamy, Li et al. 2011; Datta, Suman et al. 2012; Mukherjee, Coates et al. 2012; Snijders, Marchetti et al. 2012; Yang, Killian et al. 2015; Behjati, Gundem et al. 2016; Mavragani, Nikitaki et al. 2017). The prevalence of complex damage and double strand breaks is likely due to the density of damage delivered by ionizing radiation, but is also attributable to oxidative activity, since IR creates an oxidative state and H2O2 and other oxidizing agents can also cause (less) complex damage, double strand breaks and mutations (Seager, Shah et al. 2012; Sharma, Collins et al. 2016; Cadet, Davies et al. 2017). Radiomimetic compounds (used in chemotherapy) also cause double-strand breaks and simple complex damage. Agents like bleomycin cause double strand breaks through oxidized lesions (Regulus, Duroux et al. 2007), while agents like etoposide and cisplatin cause double strand breaks by interfering with DNA replication forks (Kawashima, Yamaguchi et al. 2017).
Evidence suggests that proliferation and inflammation are also implicated in chemical carcinogenicity. The aforementioned pubertal susceptibility implies a dependence on proliferation, as does the fact that tumorigenesis following NMU depends on proliferation during treatment (Medina 2007). Like IR, NMU and DMBA promote hyperplasia in terminal end buds and ducts and ductal carcinoma in situ leading to carcinogenesis (Goepfert, Moreno-Smith et al. 2007; Medina 2007; Imaoka, Nishimura et al. 2009; Russo 2015). In terms of inflammation, some chemical carcinogens appear to share with IR an increase in inflammatory reactions in mammary stroma and a tumor-promoting effect of stroma (Russo and Russo 1996; Barcellos-Hoff and Ravani 2000; Maffini, Soto et al. 2004; Nguyen, Oketch-Rabah et al. 2011) and although bleomycin has not been characterized for its effects on mammary stroma or mammary carcinogenesis it causes lung fibrosis (an anti-inflammatory reaction) so consistently that it is used as a research model for that endpoint (Moeller, Ask et al. 2008).
Medina, D. (2007). "Chemical carcinogenesis of rat and mouse mammary glands." Breast Dis 28: 63-68.