Alcohol stimulates estrogen receptor signaling in human breast cancer celllines

Epidemiological studies suggest that moderate alcohol consumption increases the risk of breast cancer, and that alcohol combined with estrogen replace ment therapy may synergistically enhance the risk, However, the mechanism(s ) of alcohol-induced mammary cancer is unknown. In human breast cancer cell lines, we found that ethanol (EtOH) caused a dose-dependent increase of up to 10- to 15-fold in the transcriptional activity of the liganded estrogen receptor (ER-alpha), but did not activate the nonliganded receptor. Signif icant stimulation of ER-alpha activity was observed at EtOH concentrations comparable with or less than blood alcohol levels associated with intoxicat ion and at doses below the threshold for ill vitro cytotoxicity. These find ings may be explained, in part, by an EtOH-induced down-regulation of the e xpression of BRCA1, a potent inhibitor of ER-alpha activity, and, in part, by a modest increase in the ER-alpha levels. Our findings suggest that inac tivation of BRCA1 and increased estrogen-responsiveness might contribute to alcohol-induced breast cancer.