Stanbrough M, Leav I, Kwan P W, Bubley G J, Balk S P
Cancer Biology Program, Hematology-Oncology Division, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA.
Proc Natl Acad Sci U S A. 2001 Sep 11;98(19):10823-8. doi: 10.1073/pnas.191235898. Epub 2001 Sep 4.
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, there are no animal models of AR-mediated prostatic neoplasia, and it remains unclear 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 AR transgene regulated by the rat probasin promoter (Pb) was used to generate transgenic mice expressing increased levels of AR protein in prostate secretory epithelium. The prostates in younger (<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 human high-grade prostatic intraepithelial neoplasia (PIN), a precursor to PCa. These results demonstrate that the AR is a positive regulator of cell growth in normal prostate epithelium and provide a model system of AR-stimulated PIN that can be used for assessing preventative hormonal therapies and for identifying secondary transforming events relevant to human PCa.
前列腺癌（PCa）是一种雄激素依赖性疾病，可通过雄激素剥夺疗法进行治疗，目前正在进行临床试验以通过降低雄激素受体（AR）活性来预防前列腺癌。然而，尚无AR介导的前列腺肿瘤形成的动物模型，并且尚不清楚AR在正常前列腺分泌上皮细胞生长中是正调节因子还是负调节因子。为了评估AR在前列腺上皮中的直接作用，使用由大鼠前列腺素启动子（Pb）调控的小鼠AR转基因来生成在前列腺分泌上皮中表达增加水平AR蛋白的转基因小鼠。年轻（<1岁）的Pb-mAR转基因小鼠的前列腺在组织学上是正常的，但Ki-67免疫染色显示腹侧前列腺和背外侧前列腺的上皮增殖明显增加。年老（>1岁）的转基因小鼠发展出局灶性上皮内瘤变区域，与人类高级别前列腺上皮内瘤变（PIN）非常相似，PIN是前列腺癌的前体。这些结果表明，AR是正常前列腺上皮细胞生长的正调节因子，并提供了一个AR刺激的PIN模型系统，可用于评估预防性激素疗法以及识别与人类前列腺癌相关的二次转化事件。
