A significant portion of patients who present with non-muscle invasive "superficial" bladder cancer develop the muscle "invasive" life-threatening form of the disease during subsequent follow-up. In clinical studies, overexpression of the epidermal growth factor receptor (EGFR) and the p21 ras oncogene have been strongly associated with this phenotypic tumor transition. The marked difference in incidence of invasive bladder cancer in Asia compared to the United States has made us hypothesize 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 isoflavones present in this diet may contribute to a reduction in the number of invasive transitional cell bladder cancers. In this regard, we sought to determine the effect of genistein, a naturally occurring dietary protein tyrosine kinase (PTK) inhibitor, on the growth and motility of human bladder cancer cell lines with diverse EGFR and p21ras expression phenotypes and corresponding invasive behaviors. These effects were compared with those of tyrphostin, a pure synthetic EGFR inhibitor. Our results indicate that both genistein and tyrphostin are effective inhibitors of bladder cancer motility and growth, key factors in the 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 mutated p21ras but do not overexpress the EGFR are less inhibited by these 2 compounds, suggesting that their effect is primarily directed at the EGFR signal transduction pathways proximal to the p21ras gene. Our results would seem to corroborate the notion that a high dietary intake of isoflavones is a likely explanation for the decreased incidence of invasive bladder cancer.