INHIBITION OF HUMAN BLADDER-CANCER CELL MOTILITY BY GENISTEIN IS DEPENDENT ON EPIDERMAL GROWTH-FACTOR RECEPTOR BUT NOT P21RAS GENE-EXPRESSION

A significant portion of patients who present with nonmuscle invasive ''superficial'' bladder cancer develop the muscle ''invasive'' life-th reatening form of the disease during subsequent follow-up, In clinical studies, overexpression of the epidermal growth factor receptor (EGFR ) and the p12 ras oncogene have been strongly associated with this phe notypic tumor transition. The marked difference in incidence of invasi ve bladder cancer in Asia compared to the United States has made us hy pothesize that, among other factors, dietary influences have an impact on such tumor progression. A significantly higher dietary consumption of soy products exists in Asia and has led to the notion that the iso flavones present in this diet may contribute to a reduction in the num ber of invasive transitional cell bladder cancers. In this regard, we sought to determine the effect of genistein, a naturally occurring die tary protein tyrosine kinase (PTK) inhibitor, on the growth and motili ty of human bladder cancer cell lines with diverse EGFR and p21ras exp ression phenotypes and corresponding invasive behaviors. These effects were compared with those of tyrphostin, a pure synthetic EGFR inhibit or. Our results indicate that both genistein and tyrphostin are effect ive inhibitors of bladder cancer motility and growth, key factors in t he development of muscle invasive disease. In addition, the growth and motility inhibitory effects of genistein and tyrphostin are observed preferentially in cells that overexpress the EGFR, Cells that have a m utated p21ras but do not overexpress the EGFR are less inhibited by th ese 2 compounds, suggesting that their effect is primarily directed at the EGFR signal transduction pathways proximal to the p21ras gene. Ou r results would seem to corroborate the notion that a high dietary int ake of isoflavones is a likely explanation for the decreased incidence of invasive bladder cancer. (C) 1998 Wiley-Liss, Inc.