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.
Xu
Jingwen
J
Department of Oncology, Lombardi Cancer Center, Georgetown University, 3970 Reservoir Road Northwest, Box 571469, Washington, D.C. 20057-1469, USA.
Fan
Saijun
S
Rosen
Eliot M
EM
D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004958:Estradiol / Q000494:pharmacology*; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D019398:Genes, BRCA1 / Q000502:physiology*; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000378:metabolism
D004967:Estrogens; D012333:RNA, Messenger; D004958:Estradiol