Indole-3-carbinol is a negative regulator of estrogen receptor-alpha signaling in human tumor cells

Estrogen, via its binding to the estrogen receptor (ER), plays an important role in breast cancer cell proliferation and tumor development. Indole-3-c arbinol (13C), a compound occurring naturally in cruciferous vegetables, ex hibits a potent antitumor activity via its regulation of estrogen activity and metabolism. This study was designed to determine the effect of 13C on t he potential to inhibit the ER-alpha. Using a reporter gene driven by the e strogen receptor, 13C (10-125 mu mol/L) significantly repressed the 17 beta -estradiol (E2)-activated ER-alpha signaling in a dose-dependent manner. 1 3C and breast cancer susceptibility gene 1 (BRCA1) synergistically inhibite d transcriptional activity of ER-alpha. Moreover, 13C down-regulated the ex pression of the estrogen-responsive genes, pS2 and cathepsin-D, and up-regu lated BRCA1. The inhibitory effects of 13C did not contribute to its cytoto xic effects because these activities were observed at less than toxic conce ntrations. These results further suggest that antitumor activities of 13C a re associated not only with its regulation of estrogen activity and metabol ism, but also its modulation of ER transcription activity.