Regulation of the estrogen-inducible gene expression profile by the breast cancer susceptibility gene BRCA1

The tumor suppressor gene BRCA1 functions in part as a caretaker in preserving the integrity of the genome, but also exhibits tissue- specific function by inhibiting estrogen receptor activity. Because estrogen ( E2) induces a wide range of gene expression changes ( by nongenomic and several transcriptional pathways), we sought to determine how comprehensive is the BRCA1- mediated inhibition of E2- induced gene expression alterations. Using cDNA- spotted microarrays, we identified a relatively large number of gene expression alterations ( both increased and decreased expression) in MCF- 7 cells caused by E2, some of which have been reported in previous studies. However, in the presence of exogenous wild- type BRCA1 ( wtBRCA1), the response to E2 was severely blunted, with only about 10% the number of gene expression changes as that found in the absence of wtBRCA1. Examples of these findings were confirmed by semiquantitative and quantitative RT- PCR assays. In contrast to wtBRCA1, the induction by E2 of several E2- responsive genes was not inhibited by a full- length tumor- associated mutant BRCA1 protein [ T300G ( or (61)Cys --> Gly)]. For three E2- responsive genes whose induction by E2 was inhibited by wtBRCA1, wtBRCA1 had little or no effect on the mRNA half- life in the presence of E2. Consistent with these findings, wtBRCA1 inhibited E2- stimulated proliferation of MCF- 7 cells, but wtBRCA1 failed to inhibit the proliferation of MCF- 7 cells stimulated by IGF- I. Our findings suggest that BRCA1 globally inhibits the response to estrogen in a dose- and time- dependent fashion. The implications of these findings for understanding how BRCA1 may act to restrain E2 action in vivo are considered.