ROLE OF ESTROGEN IN FAMILIAL BREAST CANCER

Breast cancers that occur in women who carry mutations of the breast cancer susceptibility gene 1 (BRCA1) are mostly estrogen receptor (ER)–negative; while those that occur in BRCA2 mutation carriers are usually ER-positive, similar to sporadic breast cancers. Despite these phenotypic differences, the evidence suggests that hormonal factors affect the risk of breast cancer in both BRCA1 and BRCA2 mutation carriers. In particular, prophylactic oophorectomy reduces breast cancer risk and the antiestrogen tamoxifen reduces the occurrence of contralateral breast cancer in both BRCA1 and BRCA2 carriers. Interestingly, while both BRCA1 and BRCA2 exert important functions in DNA repair and the maintenance of genomic integrity, cell-biologic and animal studies indicate that BRCA1 exerts an additional function in the regulation of ER activity that may, in part, explain why BRCA1 mutation carriers develop hormonally infl uenced tumor types. Here, BRCA1 binds directly to the ER and inhibits its transcriptional activity, through a specifi c posttranslational modifi cation (monoubiquitination). BRCA1 also binds to the progesterone receptor (PR) and inhibits its activity; and, in mouse models, BRCA1 loss-of-function mutations confer enhanced proliferative responses to estrogen and progesterone and an increased incidence of ER-driven mammary cancers. Finally, recent studies suggest that BRCA1 may function in mammary epithelial cell differentiation by promoting the conversion of ER-negative stem cells to ER-positive cells. Together, these experimental fi ndings are beginning to shed light on the puzzling clinical observations that hormonal manipulations can alter breast cancer risk in BRCA1 mutation carriers even though a large majority of BRCA1-related breast cancers are ER-negative.