API

Stressor: 452

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Estrogen

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Increase, DNA damage

Metabolites created through the oxidative metabolism of estrogens form pro-mutagenic adducts with guanine and adenine. These adducts rapidly undergo depurination leaving abasic sites that can contribute to point mutations or to double strand breaks and further errors if not correctly repaired prior to replication (Cavalieri, Chakravarti et al. 2006; Savage, Matchett et al. 2014; Yager 2015; Yasuda, Sakakibara et al. 2017). The metabolic cycling of the same estrogen metabolites contributes to the formation of ROS, which can oxidatively damage DNA. However, this does not appear to be the major mechanism of DNA damage by estrogen (Cavalieri, Chakravarti et al. 2006). The creation of estrogen metabolites depend on an imbalance in estrogen synthesis and metabolism. DNA damage and mutation is enhanced under conditions that promote estrogen synthesis or inhibit further metabolism including the inactivation of the DNA-damaging metabolites (Cavalieri, Chakravarti et al. 2006; Yager 2015).

Estrogen can also increase double strand breaks through a transcription and replication-dependent mechanism (Stork, Bocek et al. 2016). Estradiol increases double strand breaks and rearrangements at R-loops (RNA-DNA hybrids with an associated single-stranded DNA) formed at ERa-mediated transcription sites. This damage is dependent on Transcription-Coupled Nucleotide Excision Repair and occurs after a delay compared with the ER-independent breaks. This mechanism is a major contributor to overall double strand break formation after estrogen treatment (Stork, Bocek et al. 2016).

Estrogen also affects DNA damage less directly through effects on cell cycle checkpoint regulation and DNA repair mechanisms (Caldon 2014; Li, Chen et al. 2014; Schiewer and Knudsen 2016). It enhances some aspects of the cellular response to DNA damage including enhancing Rad51 recruitment of repair machinery but inhibits others aspects of the response including suppressing multiple regulators of cell cycle checkpoints and delaying complete repair of DSBs (Caldon 2014; Li, Chen et al. 2014). Estrogen also promotes relatively error-prone NHEJ repair mechanisms (Caldon 2014). The net effect promotes survival and replication at the expense of genomic integrity. This effect of estrogen on cell cycle and repair also serves to promote the more direct DNA damaging effects of estrogen, since several of the mechanisms by which estrogen damages DNA require replication before repair is complete (Savage, Matchett et al. 2014; Stork, Bocek et al. 2016). Interestingly, the protection against breast cancer afforded by early parity may at least partially be mediated by a change in the response to estrogen signaling to promote p53 activity and genomic integrity at the cost of proliferation (Jerry, Dunphy et al. 2010).

The effect of estrogen on cell cycle machinery is closely linked with the canonical proliferative effect of estrogen. Since replication can create DNA damage through collapse of replicative forks encountering unrepaired sites to form DSBs, the proliferative effect itself promotes DNA damage even in the absence of other mechanisms.

 

Caldon, C. E. (2014). "Estrogen signaling and the DNA damage response in hormone dependent breast cancers." Front Oncol 4: 106.

Cavalieri, E., D. Chakravarti, et al. (2006). "Catechol estrogen quinones as initiators of breast and other human cancers: implications for biomarkers of susceptibility and cancer prevention." Biochim Biophys Acta 1766(1): 63-78.

Jerry, D. J., K. A. Dunphy, et al. (2010). "Estrogens, regulation of p53 and breast cancer risk: a balancing act." Cellular and molecular life sciences : CMLS 67(7): 1017-1023.

Li, Z., K. Chen, et al. (2014). "Cyclin D1 integrates estrogen-mediated DNA damage repair signaling." Cancer Res 74(14): 3959-3970.

Savage, K. I., K. B. Matchett, et al. (2014). "BRCA1 deficiency exacerbates estrogen-induced DNA damage and genomic instability." Cancer Res 74(10): 2773-2784.

Schiewer, M. J. and K. E. Knudsen (2016). "Linking DNA Damage and Hormone Signaling Pathways in Cancer." Trends Endocrinol Metab 27(4): 216-225.

Stork, C. T., M. Bocek, et al. (2016). "Co-transcriptional R-loops are the main cause of estrogen-induced DNA damage." Elife 5.

Yager, J. D. (2015). "Mechanisms of estrogen carcinogenesis: The role of E2/E1-quinone metabolites suggests new approaches to preventive intervention--A review." Steroids 99(Pt A): 56-60.

Yasuda, M. T., H. Sakakibara, et al. (2017). "Estrogen- and stress-induced DNA damage in breast cancer and chemoprevention with dietary flavonoid." Genes Environ 39: 10




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