The phosphoinositide 3-kinase (PI3K) signaling pathway has been highly implicated in human prostate cancer on the basis of frequent loss of the tumor suppressor gene, PTEN in advanced disease. PTEN encodes a phosphatase that hydrolyzes the lipid product of PI3K, phosphatidylinositol-3,4,5-trisphosphate and loss of PTEN results in hyperactivation of the protein-Ser/Thr kinase AKT as well as other effectors of the PI3K pathway. In this project, we propose to further elucidate components of the PI3K pathway that contribute to prostate cancer. In addition, we propose to manipulate endogenous PI3K and PTEN genes and introduce oncogenic mutations of PI3K into mice in order to test the necessity and sufficiency of PI3K isoforms for development of prostate cancer. This project has three specific aims.
Aim 1 : We will attempt to identify upstream activators of PI3K in human prostate cancer cell lines and in xenograph models by immunoprecipitating PI3K and identifying co-precipitating proteins. The results of this study should reveal protein-Tyr kinase activators of PI3K that contribute to prostate cancer and that could be targeted for therapeutic intervention.
Aim 2 : We will introduce oncogenic mutants of the p110a subunit of PI3K into prostate epithelial tissue by transgene and knockin approaches and determine the effect of these mutations on prostate neoplasia and on gene expression profiles. The results of this study will be compared to our previous results with PTEN deletions and with results from mouse models being developed in the Sellers' laboratory (Project 2) and Sawyers' laboratory (Project 3) where activated genes for components downstream of the PI3K pathway are being introduced into the prostate.
Aim 3 : We will introduce a drug- inducible dominant negative form of PI3K to determine the effect of acute inhibition of this pathway on prostate tumors that develop due to loss of PTEN. In addition, we will delete specific genes for catalytic and regulatory subunits of class IA PI3K family in the prostate in the context of prostate-specific PTEN deletion in order to determine which isoforms of PI3K are critical for tumor formation. The results of this study will predict whether drugs that target specific PI3K isoforms will be effective in treating this disease.
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