Genistein: Mechanisms of action in the TRAMP model of prostate cancer

Prostate cancer (PC) is the second-leading cause of cancer deaths in U.S. men. The incidence of localized PC is similar between U.S. and Asian men, but advanced PC incidence is lower in Asian men. This incidence increases in Asian men upon immigration to the United States. Their transition from a high soy diet to one high in fat may be the cause. Genistein, a component of soy, has been proposed as a possible chemopreventive agent. In vitro and in vivo studies have shown that genistein inhibits the growth of PC cells. Hence, our objectives were to further test the hypothesis that genistein prevents progression of PC by utilizing the transgenic adenocarcinoma mouse prostate (TRAMP) model of prostate cancer and to explore cell adhesion-mediated mechanisms by which genistein prevents progression of prostate tumors to metastatic growth. At 5--6 weeks of age, mice were put on diets containing varying levels of genistein: 0, 250, or 500-mg genistein/kg AIN-76A diet for 12, 18, 24 or 28 weeks. Upon necropsy, the dorsolateral prostate of each mouse was collected, weighed, and frozen for reverse-transcriptase polymerase chain reaction (RT-PCR) analysis of our genes of interest: osteopontin (OPN), alphav, and beta 3 subunit of integrins. Portions of the prostate and lymph node were also fixed for histopathological analysis, and mortality data was recorded for the overall study. Our studies confirmed that TRAMP mice display the progressive stages of PC as they age. Genistein significantly reduced the weight of poorly differentiated (PD) prostates but did not significantly reduce the weight of the lymph nodes, despite the dose-dependent trend observed. Elevated OPN transcript levels were only present in PD prostates. The mRNA levels of OPN, an extracellular phosphoprotem associated with advanced prostate cancer, were downregulated in genistein-treated mice. However, genistein had no effect on transcript levels of the alphav and beta3 subunit of integrins that serve as one of the pairs of receptors for OPN. Moreover, genistein had a beneficial effect on incidence and mortality. Genistein also altered apoptosis. A positive correlation between lymph node weight and OPN transcript levels was also observed. These results demonstrate that genistein may serve as a chemopreventive agent for prevention of the progression of prostate cancer to the advanced stage.