The central question being addressed by this project is whether inhibition of phosphoinositide 3-kinase (PI3K) is a rational approach for treating human prostate cancers. PI3K has been implicated in prostate cancer because of the recent discovery that the PTEN/MMAC1 tumor suppressor gene encodes a phosphatase that hydrolyzes the lipid products of PI3K. Loss of PTEN correlates with high Gleason grade prostate tumors. Prostate cancer cell lines that lack PTEN have constitutive activation of enzymes downstream of PI3K, including the AKT protein-Ser/Thr kinase and reintroduction of PTEN (or addition of PI3K inhibitors) blocks this pathway and leads to decreased cell and increased apoptosis. Although studies with cell lines suggest that inhibition of PI3K should inhibit growth and survival of tumors that result from loss of PTEN, there is no evidence that this is true at the animal level. In this project, we intend to test the importance that result from loss of PTEN for prostate tumor development in mice. Mice that are hemizygotic for PTEN are viable and develop a variety of tumors, including adenocarcinoma or the prostate. We will delete genes for the p85 regulatory subunits of PI3K and determine whether this impairs prostate tumor development in the PTEN+/- mice. We will coordinate these studies with the aims Projects 2 and 3 by Dr. Roberts and Dr. Sellers where genes for the catalytic subunit of PI3K and for downstream enzymes (AKT) will be manipulated in mice. Prostate-specific and regulated deletion of the PTEN gene and the PI3K genes will allow us to circumvent complexities that result from germline loss of these genes. The prostates from the various mouse models will be examined for hyperplasia and adenocarcinomas and will be characterized for the activation state of enzymes in the PI3K pathway. In addition, DNA microarrays will be used to investigated gene clusters that change expression in response to activation or inhibition of the PI3K pathway. These studies will provide an understanding of the role of PI3K in prostate cancer development, new approaches for evaluating human tumors for activation of this pathway, and an assessment of the efficacy of targeting PI3K catalytic or regulatory subunits for prostate chemotherapy.
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