GENISTEIN EXERTS MULTIPLE SUPPRESSIVE EFFECTS ON HUMAN BREAST-CARCINOMA CELLS

Dietary genistein, a natural flavone compound found in soy, has been p roposed to be responsible for the low rate of breast cancer in Asian w omen. The cellular mechanisms of genistein's chemopreventive effects i n vivo have been largely unexplored. In our previous studies, we found that genistein exerted pronounced antiproliferative effects on both e strogen receptor-positive and -negative human breast carcinoma cells t hrough G(2)-M arrest, induction of p21(WAF1/CIP1) expression, and apop tosis. Because chemopreventive effects need not be limited to antiprol iferation, we decided to examine whether genistein exerted other suppr essive effects on breast carcinoma progression. Genistein inhibited in vasion in vitro of MCF-7 and MDA-MB-231 cells. This inhibition was cha racterized by down-regulation of MMP (matrix metalloproteinase)-9 and up-regulation of tissue inhibitor of metalloproteinase-1, the former o f which was transcriptionally regulated at activation protein-1 sites in the MMP-9 promoter. Genistein's in vitro effects on MMP-9 and tissu e inhibitor of metalloproteinase-1 were also demonstrated in in vivo s tudies in nude mouse xenografts of MDA-MB-231 and MCF-7 cells. In thes e xenograft studies, genistein inhibited tumor growth, stimulated apop tosis, and up-regulated p21(WAF1/CIP1) expression. In the MDA-MB-231 x enograft, genistein also inhibited angiogenesis by decreasing vessel d ensity and decreasing the levels of vascular endothelial growth factor and transforming growth factor-beta 1. These in vitro and in vivo stu dies demonstrate that genistein exerts multiple suppressive effects on breast carcinoma cells, suggesting that its mechanism of chemoprevent ion is pleiotropic.