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 tyrosine kinase inhibitor and prominent isoflavonoid in soy products and has been proposed as the agent responsible for lowering the rate of breast cancer in Asian women. We have previously shown that genistein inhibits the growth of MDA-MB-231 breast cancer cells, regulates the expression of apoptosis-related genes, and induces apoptosis through a p53-independent pathway. In this study, we investigated these effects of genistein in the breast cancer cell 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 effected 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 lines when treated with genistein, as measured by DNA laddering, poly(ADP-ribose) polymerase (PARP) cleavage, and flow cytometric analysis. We also found an up-regulation of Bax and p21WAF1 expression and down-regulation of Bcl-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 these 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 findings suggest that genistein may be a potentially effective chemopreventive or therapeutic agent against breast cancer.
Li
Y
Y
Department of Pathology, Karmanos Cancer Institute at Wayne State University School of Medicine, Detroit, MI 48201, USA.
Bhuiyan
M
M
Sarkar
F H
FH
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D019833:Genistein / Q000627:therapeutic use*; D006801:Humans; D008666:Metalloendopeptidases / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured; D051028:bcl-2-Associated X Protein
D000970:Antineoplastic Agents; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004791:Enzyme Inhibitors; D019833:Genistein; D008666:Metalloendopeptidases; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D018719:Erb-b2 Receptor Tyrosine Kinases; D051028:bcl-2-Associated X Protein; C494826:BAX protein, human; C493956:CDKN1A protein, human