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 car cinogenesis whose inhibition may represent preventive intervention. In dole-3-carbinol (13C), a glucosinolate metabolite from cruciferous veg etables, inhibits organ site carcinogenesis in rodent models. Clinical ly relevant biochemical and cellular mechanisms for the anticarcinogen ic effects of 13C, 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) 13C inhibits aberrant proliferation in initiated and transformed cells, and (ii) I nhibition of aberrant proliferation is associated with altered cell-cy cle progression, estradiol (E-2) metabolism, and apoptosis. Aberrant p roliferation in 184-B5/BP, 184-B5/HER, and MDA-MB-231 cells was eviden t by a 55%-67% decrease in the ratio of quiescent (Q = GO) to prolifer ative (P = S + M) phase of the cell cycle, a 72%-90% decrease in apopt osis, and a 76%-106% increase in anchorage-dependent growth, These cel ls also exhibited a 88%-90% decrease in the ratio of C2 to C16 alpha-h ydroxylation products of E-2. Treatment of 184-B5/ BP, 184-B5/HER, and MDA-MB-231 cells to cytostatic dose of 50 mu M 13C resulted in an 137 %-210% increase in Q/P 13C ratio, a 4- to 18-fold increase in E-2 meta bolite ratio, a 2-fold increase in cellular apoptosis, and a 54%-61% i nhibition of growth, The preventive efficacy of 13C on human mammary c arcinogenesis may be due in part to its ability to regulate cell-cycle progression, increase the formation of antiproliferative E-2 metaboli te, and induce cellular apoptosis.