Genistein activates p38 mitogen-activated protein kinase, inactivates ERK1/ERK2 and decreases Cdc25C expression in immortalized human mammary epithelial cells

Genistein (4',5,7-trihydroxyisoflavone) is an isoflavonoid present in soybeans that exhibits anticarcinogenic effects in breast, colon and prostate cancer cells. We recently reported that-genistein treatment of the immortalized but nonmalignant human mammary epithelial cell line MCF-10F resulted in growth arrest of MCF-10F cells in the G2 phase of the cell cycle, a large induction of the Tyr15 phosphorylation of Cdc2 (along with decreased activity of Cdc2), increased expression of p21(waf/cip1) and decreased expression of the cell cycle phosphatase Cdc25C. In the present study of MCF-10F cells, genistein rapidly and significantly activated p38, inactivated ERK1/ERK2 and had no effect on SAPK/JNK activity. We also showed that p38 is involved in genistein-induced changes in Cdc2 phosphorylation and that the downregulation of Cdc25C expression by genistein is through the p38 pathway. Finally, we provided evidence that the p38 pathway is involved in genistein-inhibited cell proliferation. These data suggest an important interplay between the p38 pathway and G2 cell cycle checkpoint control and provide insights into possible mechanisms whereby this isoflavone may inhibit early events in mammary carcinogenesis.