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.

Keywords: BRCA1; DDR; DNA damage response; DNA repair; breast cancer; estrogen receptor; p53; tamoxifen.

Figure 1

Key effectors of the DNA damage response and DNA repair that intersect with estrogen receptor α signaling. The DNA damage response (DDR) is a series of pathways that recognize and process DNA damage. After DNA damage recognition, signals are transduced and amplified through kinase activation (ATM, ATR, DNA-PK, CHK1, and CHK2) to downstream effectors (e.g., p53 and BRCA1) that facilitate DNA repair, apoptosis, and cell cycle arrest. Estrogen receptor α (ERα) exists in complex with multiple members of the DDR and DNA repair pathways (e.g., DNA-PK, BRCA1, p53, and MDM2). These protein:protein interactions are denoted by ERα represented as a hexagon. This includes c-Abl, a multi-functional regulator of the DDR and its downstream pathways (14). ERα also transcriptionally regulates or is regulated by other members of these pathways (e.g., ATM, ATR, CHK1, BRCA2, and DNA damage checkpoint protein Rad17), denoted by red lines. ERα signaling antagonizes two major endpoints of DDR action: apoptosis and cell cycle arrest (red lines).