Most current transgenic mouse models of prostate cancer suffer from the drawback that the initiating oncogene (the SV40 T antigen) has no known role in the pathogenesis of the human disease. Thus it is critical to generate an improved murine model of prostate cancer that is based on the genetic lesions commonly observed in human prostate carcinoma. Two of the most common chromosomal aberrations observed in prostate carcinoma cells include loss of sequences from the short arm of chromosome 8 and gain of sequences on its long arm. A strong candidate for a tumor suppressor located at 8p21 is Nkx3.1, a homeobox- containing protein whose expression is lost in many prostate tumors and prostatic intraepithelial neoplasia (PIN) lesions. We have used Cre/loxP-mediated recombination to generate mice with deletion of Nkx3.1 in the adult prostate. These mice develop preinvasive PIN lesions. The Myc oncogene maps to 8q24, and is the target for amplification in many prostate tumors. Overrepresentation of Myc gradually increases in PIN lesions, primary carcinomas and metastases, indicating that Myc overexpression is associated with tumor progression. Intriguingly, gain of 8q24 is often accompanied by loss of 8p21 in prostate carcinomas, and concurrent loss of 8p and gain of 8q is associated with poor patient prognosis. The overall goal of this proposal is to generate and characterize mice with conditional loss of Nkx3.1 and gain of Myc in the adult prostate. We hypothesize that cooperation between loss of Nkx3.1 and gain of Myc will result in the progression of PIN lesions to invasive carcinoma and ultimately metastatic disease. The following Specific Aims are proposed: 1) To generate and characterize transgenic mice that overexpress Myc upon Cre- mediated recombination in the prostate. 2) To generate and characterize mice with concurrent loss of Nkx3.1 and overexpression of Myc in the prostate. 3) To examine the genetic pathways altered in prostate tumorigenesis in these models, with particular emphasis on pathways known to be commonly altered in human prostate carcinoma. This proposal seeks to develop an in vivo genetic model of prostate cancer that recapitulates the human disease. This will provide an important tool for studying the molecular events that lead to prostate cancer.
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