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Submitted on March 30, 2004
Accepted on December 30, 2004
Department of Oncology, Lombardi Cancer Center, Georgetown University, 3970 Reservoir Road, NW, Washington, DC 20057
* To whom correspondence should be addressed. E-mail: emr36{at}georgetown.edu.
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. Since estrogen (E2) induces a wide range of gene expression changes (by non-genomic 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% of the number of gene expression changes as found in the absence of wtBRCA1. Examples of these findings were confirmed by semi-quantitative 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 61Cys 
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 proliferation of MCF-7 cells stimulated by insulin-like growth factor-1 (IGF-1). 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.
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