Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
Oncogene. 2011 Oct 20;30(42):4327-38. doi: 10.1038/onc.2011.144. Epub 2011 May 2.
Prostate cancer and breast cancer are the most common malignancies in the western world. Androgen receptor (AR) and PTEN both have been well documented to have important roles in prostate carcinogenesis. In contrast, AR and PTEN in breast carcinogenesis have not been well studied. Furthermore, the crosstalk and connection between those two pathways remain unclear. Increased AR expression in prostate cancers, combined with decreased PTEN expression, portends a poor clinical outcome. Paradoxically, both high AR and high PTEN levels, detected by immunohistochemistry, in primary breast carcinomas have been associated with better disease-free survival. Here, we performed in silico analysis of publicly available microarray data sets from prostate or breast carcinomas. We found an inverse correlation between AR and PTEN transcript expression in prostate cancer tissues in contrast to the positive correlation in breast cancer. These data led us to hypothesize that AR may directly affect PTEN transcriptional regulation in prostate and breast cancer cells. Here, we show for the first time that AR inhibits PTEN transcription in prostate cancer cells, whereas AR upregulates PTEN transcription in breast cancer cells, which mechanistically explains both the immunohistochemical PTEN-AR expressional data noted in clinical trials and in our in silico analysis of the transcriptomes of breast and prostate cancers. In addition, we have fine-mapped the AR-binding motif within the PTEN promoter. Here we show that, in patients with Cowden syndrome, an inherited cancer syndrome caused by germline mutations scattered throughout PTEN, point variants affecting the 3' end of the AR-binding motif result in abrogation of androgen-mediated transcriptional regulation of PTEN expression. We may speculate that the differential AR effect on PTEN may begin to explain organ-specific and perhaps sex-specific neoplasia predisposition in Cowden syndrome, as well as why only a fraction of women with germline PTEN mutations develop breast cancer, depending on the androgen steroid milieu and levels.
前列腺癌和乳腺癌是西方世界最常见的恶性肿瘤。雄激素受体（AR）和 PTEN 都已被证明在前列腺癌发生中具有重要作用。相比之下，AR 和 PTEN 在乳腺癌发生中的作用尚未得到充分研究。此外，这两条途径之间的相互作用和联系仍不清楚。前列腺癌中 AR 表达增加，同时 PTEN 表达降低，预示着临床结局不佳。矛盾的是，原发性乳腺癌中免疫组化检测到的高 AR 和高 PTEN 水平与无病生存时间延长有关。在这里，我们对来自前列腺癌或乳腺癌的公开微阵列数据集进行了计算机分析。我们发现，与乳腺癌中的正相关相反，在前列腺癌组织中 AR 和 PTEN 转录表达呈负相关。这些数据使我们假设 AR 可能直接影响前列腺和乳腺癌细胞中 PTEN 的转录调节。在这里，我们首次表明 AR 抑制前列腺癌细胞中的 PTEN 转录，而 AR 上调乳腺癌细胞中的 PTEN 转录，这从机制上解释了临床试验中观察到的免疫组化 PTEN-AR 表达数据以及我们对乳腺癌和前列腺癌转录组的计算机分析。此外，我们已经在 PTEN 启动子内精细地绘制了 AR 结合基序。在这里，我们表明，在 Cowden 综合征患者中，一种由 PTEN 中散在的种系突变引起的遗传性癌症综合征，影响 AR 结合基序 3' 末端的点突变导致雄激素介导的 PTEN 表达转录调节被废除。我们可以推测，AR 对 PTEN 的不同影响可能开始解释 Cowden 综合征中器官特异性和可能性别特异性肿瘤易感性，以及为什么只有少数患有种系 PTEN 突变的女性会患上乳腺癌，这取决于雄激素类固醇环境和水平。
