There is a need for murine prostate cancer (PCa) models that reflect events occurring early in the disease process in humans. Unfortunately, PCa susceptibility genes or other early events contributing to the development of PCa have not been clearly defined. However, the androgen receptor (AR) plays a critical role in prostatic carcinogenesis, with the vast majority of PCa being androgen dependent. The AR also fulfills some of the criteria for a PCa susceptibility gene, as increased AR activity appears to be a risk factor for PCa development. Nonetheless, the AR does not stimulate the growth of normal prostate epithelium in vitro and some effects of androgens on the epithelium in vivo are mediated indirectly through prostate stromal cells. Therefore, while the AR is clearly a direct positive regulator of PCa growth, its functions with respect to growth in normal prostate epithelium have been uncertain. To directly assess the role of the AR in normal prostate epithelium, mice with increased AR expression in these cells were generated using a probasin promoter regulated murine AR transgene (Pb-mAR mice). The proliferative rate in prostate epithelium from Pb-mAR mice was markedly increased, and older mice developed high grade prostatic intraepithelial neoplasia (PIN), a precursor lesion to PCa in humans. These findings demonstrate that the AR is a direct positive regulator of prostate epithelial cell growth and provide a model of AR dependent prostate carcinogenesis that is consistent with human PCa. We propose to use these Pb-mAR mice as a model to identify early AR mediated events in prostate carcinogenesis, to identify subsequent genetic or epigenetic events that promote the development of PCa, and to develop PCa models through the introduction of additional defined genetic defects.
The specific aims are: 1) Define the mechanisms of increased proliferation in Pb-mAR prostate epithelium; 2) Test the hypotheses that loss of p27 or RB, or gain of bcl2, can drive the development of intraepithelial neoplasia in Pb-mAR mice; and 3) Test the hypothesis that activation of MAP kinase and PI3 kinase pathways can drive the development of invasive PCa in Pb-mAR mice or immunodeficient mice.
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