DESCRIPTION (Applicant's Description): Research Plan: The main goal of this proposal is to define how the PTEN phosphatase acts to suppress tumor formation and to exploit this knowledge to design novel therapeutic approaches to prostate cancer. Our preliminary studies have established that PTEN expression is frequently lost in prostate cancer at the transcriptional level and that PTEN loss in tumor cells leads to excess cell survival signaling. In Aim 1, we will test the role of membrane localization on PTEN function by determining the effect of membrane targeted mutants of PTEN. In Aim 2, we will investigate the role of PTEN in mediating sensitivity to apoptosis induced by detachment from matrix, known as anoikis. We will characterize the effect of PTEN in sensitizing prostate tumor cells to anoikis and investigate the mechanisms of anoikis induction. In Aim 3, we will characterize the effect of PTEN expression in sensitizing cancer cells to a p optotic stimuli in vitro and investigate the effect of PTEN on tumorigenicity and sensitivity to chemotherapy and androgen deprivation in vivo in a prostate cancer xenograft animal model. This project will test the hypothesis that reconstitution of PTEN expression will reverse resistance to m u ltiple apoptotic stimuli associated with prostate cancer cells and represents a novel strategy for enhancing the efficacy of prostate cancer treatment.