Loss of Nkx3.1-an Initiating Event in Prostate Cancer

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DESCRIPTION (provided by applicant): Prostate cancer is the most common non-skin cancer in men and the second-leading cause of death from cancer in the US. As with most human cancers, prostate tumorigenesis requires the sequential accumulation of multiple genetic lesions. The multistep nature of tumorigenesis is widely accepted; however little is known about the initiation steps that lead to pre-malignant alterations. Haploinsufficiency at tumor suppressor loci presents a potential central mechanism for tumor initiation. In the prostate, tumor initiation is often linked to loss-of-heterozygosity at the NKX3.1 locus. In mice, haploid loss ofNkx3.1, which encodes a homeodomain protein, is sufficient to cause prostate epithelial hyperplasia and eventual PIN formation. In both the Myc overexpression and Pten loss-of-function mouse models of prostate cancer, Nkx3.1 expression is lost in the early stages of tumorigenesis. Our central hypothesis is that NKXS.1 serves a 'gatekeeper' function in the prostate and that its loss is a major initiating event in prostate cancer. To test this hypothesis, we plan to investigate whether overexpression of NKX3.1 in the prostate can prevent the development of prostate cancer in several mouse models. We will also attempt to identify effectors of NKX3.1 that would provide a link between it and abnormal proliferation. For this search, we will identify genes that are directly regulated by NKX3.1 through a series of analyses including expression profiling, comparative genomic analysis chromatin immunoprecipitation and reporter gene assays. Finally, we will determine whether the effects of NkxS.1 loss on prostate epithelial cell proliferation are mediated through alterations in mTOR activation. We will also attempt to prevent hyperplasia in Nkx3.1 -deficient mice using mTOR inhibitors. For these studies, we will utilize a combination of techniques, including computational techniques, lentivirus mediated overexpression and knockdown using siRNA, mutagenesis, and functional assays conducted in vitro and using transgenic mice.