Abrogation of estrogen-mediated cellular and biochemical effects by indole-3-carbinol

The use of naturally occurring phytoantiestrogens for prevention and therapy of breast cancer is an alternative to synthetic antiestrogens. We have been examining the mechanism of action of the antiestrogen indole-3-carbinol (I3C), a constituent of compounds present in cruciferous vegetables. I3C abrogates the cell-proliferative effect of 17beta-estradiol (E-2) as observed in several different estradiol-responsive breast cancer cell lines and isolated cell clones. Modulation of E, activity by I3C, in part, was by the induction of the 2-hydroxylation pathway, one of the two competing hydroxylation pathways of estrone conversion that resulted in the formation of metabolites with antiestrogenic properties. I3C-mediated induction of the 2-hydroxylation pathway correlated with a selective induction of cytochrome P-450 1A1 by I3C in E-2-responsive human breast cancer cells. Induction of neither the 2-hydroxylation pathway nor cytochrome P-450 1A1 was observed in estrogen-nonresponsive human breast cancer cells. This selective effect warranted a further search for biochemical targets Of I3C related to E-2 function. To this end, we observed that E-2-mediated phosphorylation of the estrogen receptor is inhibited by I3C. Our results are consistent with the hypothesis that BC exerts its antiestrogenic effect by intervention in the E-2-estrogen receptor signal transduction pathways and by alterations in E-2 metabolism that resulted in the formation of metabolites with antiestrogenic activity.