Induction of apoptosis and inhibition of c-erbB-2 in MDA-MB-435 cells by genistein

Breast cancer is the most common cancer and second leading cause of cancer related deaths in women in the United States. Genistein is a protein tyrosi ne kinase inhibitor and prominent isoflavonoid in soy products and has been proposed as the agent responsible for lowering the rate of breast cancer i n Asian women. We have previously shown that genistein inhibits the growth of MDA-MB-231 breast cancer cells, regulates the expression of apoptosis-re lated genes, and induces apoptosis through a p53-independent pathway. In th is study, we investigated these effects of genistein in the breast cancer c ell line MDA-MB-435 and 435.eB cells that were established by transfecting c-erbB-2 cDNA into MDA-MB-435. We also investigated the effect of genistein on matrix metalloproteinase (MMP) secretion previously shown to be effecte d by erbB-2 transfection. Genistein was found to inhibit MDA-MB-435 and 435 .eB cell growth. Induction of apoptosis was also observed in these cell lin es when treated with genistein, as measured by DNA laddering, poly(ADP-ribo se) polymerase (PARP) cleavage, and flow cytometric analysis. We also found an up-regulation of Bar and p21(WAF1) expression and down-regulation of Bc l-2 and c-erbB-2 in genistein-treated cells. Gelatin zymography showed that genistein inhibits the secretion of MMP in the breast cancer cells. From t hese results, we conclude that genistein inhibits the growth of MDA-MB-435 breast cancer cells, induces apoptosis, regulates the expression of genes, and may inhibit invasion and metastasis of breast cancer cells. These findi ngs suggest that genistein may be a potentially effective chemopreventive o r therapeutic agent against breast cancer.