Inhibition of proliferation and modulation of estradiol metabolism: novel mechanisms for breast cancer prevention by the phytochemical indole-3-carbinol.

Aberrant proliferation is an early-occurring intermediate event in carcinogenesis whose inhibition may represent preventive intervention. Indole-3-carbinol (I3C), a glucosinolate metabolite from cruciferous vegetables, inhibits organ site carcinogenesis in rodent models. Clinically relevant biochemical and cellular mechanisms for the anticarcinogenic effects of I3C, however, remain unclear. Experiments were conducted on reduction mammoplasty derived 184-B5 cells initiated with chemical carcinogen (184-B5/BP) or with oncogene (184-B5/HER), and on mammary-carcinoma-derived MDA-MD-231 cells to examine whether (i) I3C inhibits aberrant proliferation in initiated and transformed cells, and (ii) inhibition of aberrant proliferation is associated with altered cell-cycle progression, estradiol (E2) metabolism, and apoptosis. Aberrant proliferation in 184-B5/BP, 184-B5/HER, and MDA-MB-231 cells was evident by a 55%-67% decrease in the ratio of quiescent (Q = G0) to proliferative (P = S + M) phase of the cell cycle, a 72%-90% decrease in apoptosis, and a 76%-106% increase in anchorage-dependent growth. These cells also exhibited a 88%-90% decrease in the ratio of C2 to C16alpha-hydroxylation products of E2. Treatment of 184-B5/BP, 184-B5/HER, and MDA-MB-231 cells to cytostatic dose of 50 microM I3C resulted in an 137%-210% increase in Q/P I3C ratio, a 4- to 18-fold increase in E2 metabolite ratio, a 2-fold increase in cellular apoptosis, and a 54%-61% inhibition of growth. The preventive efficacy of I3C on human mammary carcinogenesis may be due in part to its ability to regulate cell-cycle progression, increase the formation of antiproliferative E2 metabolite, and induce cellular apoptosis.