Estrogen Signaling and the DNA Damage Response in Hormone Dependent Breast Cancers

Abstract

Estrogen is necessary for the normal growth and development of breast tissue, but high levels of estrogen are a major risk factor for breast cancer. One mechanism by which estrogen could contribute to breast cancer is via the induction of DNA damage. This perspective discusses the mechanisms by which estrogen alters the DNA damage response (DDR) and DNA repair through the regulation of key effector proteins including ATM, ATR, CHK1, BRCA1, and p53 and the feedback on estrogen receptor signaling from these proteins. We put forward the hypothesis that estrogen receptor signaling converges to suppress effective DNA repair and apoptosis in favor of proliferation. This is important in hormone-dependent breast cancer as it will affect processing of estrogen-induced DNA damage, as well as other genotoxic insults. DDR and DNA repair proteins are frequently mutated or altered in estrogen responsive breast cancer, which will further change the processing of DNA damage. Finally, the action of estrogen signaling on DNA damage is also relevant to the therapeutic setting as the suppression of a DDR by estrogen has the potential to alter the response of cancers to anti-hormone treatment or chemotherapy that induces DNA damage.

Breast Cancer Risk Associated with Estrogen Exposure and Truncating Mutation Location inBRCA1/2Carriers

“…Our results suggested a variation in breast cancer risk associated with parity according to the location of the mutation in BRCA1, that is, a loss of the protective effect of parity when the mutation fell in the N-terminal and the C-terminal regions. This observation was consistent with the hypothesis of the BRCA1 cellular antiproliferative effect via inhibition of the transcriptional activity of estrogen receptor a through protein-protein interaction in these regions (22)(23)(24)(25). Therefore, we hypothesize that variation may also exist for the effect of factors related to exposure to estrogens, either endogens or exogens, like age at menarche, menopausal status, BMI, OC, and HRT use.…”

Robust homology-directed repair within mouse mammary tissue is not specifically affected by Brca2 mutation

“…Our results instead suggest that a greater reliance on HDR to repair DSBs may magnify the effect of BRCA2 deficiency, making the mammary epithelium more predisposed to tumorigenesis. Whether an increased reliance on HDR is due to cycles of proliferation leading to replication-associated DNA damage and possibly other sources of DNA damage, as from estrogen3738, is unclear.…”

Homology-Directed Repair and the Role of BRCA1, BRCA2, and Related Proteins in Genome Integrity and Cancer

“…In addition to a higher reliance on HDR, another non–mutually exclusive possibility is that breast and ovarian tissues may provide a supportive microenvironment to prevent the otherwise lethal effects of BRCA loss, for example, through growth-stimulating hormonal signaling. Other hypotheses include increased DNA damage from estrogen exposure (Caldon 2014, Stork et al 2016), which may lead to enhanced LOH at the BRCA1 / 2 loci in breast and ovarian tissue.…”