BACKGROUND. Epidemiological reports suggest that Asians consuming a diet high in soy have a low incidence of prostate cancer. In animal models, soy and genistein have been demonstrated to suppress the development of prostate cancer. In this study, we investigate the mechanism of action, bioavailability, and potential for toxicity of dietary genistein in a rodent model. METHODS. Lobund-Wistar rats were fed a 0.025-1.0-mg genistein/g AIN-76A diet. The dorsolateral prostate was subjected to Western blot analysis for expression of tyrosinephosphorylated proteins, and of the EGF and ErbB2/Neu receptors. Genistein concentrations were measured from serum and prostate using HPLC-mass spectrometry. Body and prostate weights, and circulating testosterone levels, were measured. RESULTS. Increasing concentrations of genistein in the diet inhibited tyrosinephosphorylated proteins with molecular weights of 170,000 and 85,000 in the dorsolateral prostate. Western blot analysis revealed that the 1-mg genistein/g AIN-76A diet inhibited by 50% the expression of the EGF receptor and its phosphorylation. In rats fed this diet, serumfree and total genistein concentrations were 137 and 2,712 pmol/ml, respectively. The free and total genistein IC 50 values for the EGF receptor were 150 and 600 pmol/g prostate tissue, respectively. Genistein in the diet also inhibited the ErbB2/Neu receptor. Body and dorsolateral prostate weights, and circulating testosterone concentrations, were not adversely effected from exposure to genistein in the diet for 3 weeks. CONCLUSIONS. We conclude that genistein in the diet can downregulate the EGF and ErbB2/Neu receptors in the rat prostate with no apparent adverse toxicity to the host. The concentration needed to achieve a 50% reduction in EGF receptor expression can be achieved by eating a diet high in soy products or with genistein supplementation. Genistein inhibition of the EGF signaling pathway suggests that this phytoestrogen may be useful in both protecting against and treating prostate cancer.