Prostatic intraepithelial neoplasia in mice expressing an androgen receptor transgene in prostate epithelium

Prostate cancer (PCa) is an androgen dependent disease that can be treated by androgen ablation therapy, and clinical trials are under way to prevent PCa through the reduction of androgen receptor (AR) activity. However, ther e are no animal models of AR-mediated prostatic neoplasia, and it remains u nclear whether the AR is a positive or negative regulator of cell growth in normal prostate secretory epithelium. To assess the direct effects of the AR in prostate epithelium, a murine AIR transgene regulated by the rat prob asin promoter (Pb) was used to generate transgenic mice expressing increase d levels of AR protein in prostate secretory epithelium. The prostates in y ounger (<1 year) Pb-mAR transgenic mice were histologically normal, but Ki- 67 immunostaining revealed marked increases in epithelial proliferation in ventral prostate and dorsolateral prostate. Older (>1 year) transgenic mice developed focal areas of intraepithelial neoplasia strongly resembling hum an high-grade prostatic intraepithelial neoplasia (PIN), a precursor to PCa . These results demonstrate that the AR is a positive regulator of cell gro wth in normal prostate epithelium and provide a model system of AR-stimulat ed PIN that can be used for assessing preventative hormonal therapies and f or identifying secondary transforming events relevant to human PCa.