BRCA1 EXPRESSION IS NOT DIRECTLY RESPONSIVE TO ESTROGEN

Expression of the breast cancer susceptibility gene, BRCA1, is induced by 17-beta estradiol (E(2)) in estrogen receptor containing breast ca ncer cell lines, Our previous studies have shown that BRCA1 transcript ion is also regulated with the cell cycle, reaching maximal levels jus t before the onset of DNA synthesis, In this study, we have examined w hether the estrogen induction of BRCA1 is direct or is a result of the mitogenic activity of the hormone, Four lines of evidence lead us to conclude that E(2) induces BRCA1 primarily through an increase in DNA synthesis: (1) The kinetics and magnitude of induction are different f rom the directly E(2) inducible gene, pS2; (2) Induction of BRCA1, but not pS2, is blocked by cycloheximide indicating that de novo protein synthesis is required; (3) Other hormonal and growth factor treatments that induce DNA synthesis have a similar effect, including IGF-1, EGF and DNA synthetic flares induced by tamoxifen and retinoic acid; (4) BRCA1 genomic fragments near the 5' end of the gene containing putativ e estrogen response elements fail to respond to E(2) when transfected into breast cancer cell lines, The most consistent explanation for the se findings and other published studies is that BRCA1 transcription is induced as a result of the mitogenic activity of E(2) in estrogen rec eptor positive cells.