Bile acids upregulate BRCA1 and downregulate estrogen receptor 1 gene expression in ovarian cancer cells
Two major risk factors for ovarian cancer include loss-of-function mutations in the BRCA1 (breast cancer 1, early onset) gene and aspects of estrogen metabolism. Modulation of the levels of the normal BRCA1 allele and estrogen receptor expression may therefore be a preventive strategy. Consensus binding motifs for the bile acid-responsive transcription factor farnesoid X receptor were identified in the BRCA1 and estrogen receptor 1 (ESR1) and estrogen receptor 2 (ESR2) genes, supported by chromatin immunoprecipitation sequencing data. Two major bile acids, deoxycholic acid (DCA) and chenodeoxycholic acid (CDCA), resulted in a greater than four-fold induction of BRCA1 transcript levels at 10 μmol/l and a greater than six-fold induction at 50 μmol/l relative to untreated control OVCAR3 ovarian cancer cells. Conversely, CDCA and DCA at 10 μmol/l resulted in about a 75% decrease in ESR1 expression in response to 10 μmol/l CDCA and DCA and close to 90% reduction with 50 μmol/l CDCA and DCA. Bile acids had no effects on ESR2 gene transcript levels. The inverse regulation of BRCA1 and ESR1 gene expression in response to physiological levels of bile acids could have important implications for disease penetrance and chemoprevention strategies in carriers of BRCA1 mutations.