Soy consumption may prevent prostate cancer and be beneficial for patients with this cancer. However, there are contradictory data on the anticancer effects of the soy isoflavone genistein, which has antioxidant properties and can affect cell proliferation and apoptosis of cancer cells through multiple mechanisms, including estrogen receptor- mediation. Genistein also affects the expression of the manganese superoxide dismutase (MnSOD) gene and polymorphisms in this gene are related to risk of prostate cancer. This proposal addresses the hypothesis that the proliferative or inhibitory effects of physiological concentrations of genistein on prostate cancer cells are dependent on their MnSOD genotype and ER- status, as well as on oxidative stress levels. To test this hypothesis, we will determine how genistein acts on prostate cancer cells with different MnSOD variants and ER- expression in a controlled oxidative stress environment with these Specific Aims: (1) Determine the influence of ER- expression on the effects of physiological genistein concentrations on cell proliferation and apoptosis. Physiological concentrations of genistein will be used in controlled ROS environments in cells with specific MnSOD genotypes. (2) Determine the influence of MnSOD genotype on the effects of genistein on cell proliferation and apoptosis of prostate cancer cells expressing different MnSOD variants, while controlling their ER- status and the ROS environment. (3) Determine the effects of genistein on prostate cancer cell proliferation and apoptosis at varying input levels of reactive oxygen species (O2.-), while controlling ER- status and MnSOD genotype. The results of this proposal will provide preliminary data for an R01 application for further studies in animal models relevant to soy consumption in therapeutic and chemopreventive settings with a focus on non-linear dose-response relationships contrasting potential benefit with possible harm of genistein.