Identification of PHLPP1 as a tumor suppressor reveals the role of feedback compensation in PTEN-mutant prostate cancer progression

Hyper-activation of the PI 3-Kinase/ AKT pathway is a driving force of many cancers. Here we identify the AKT-inactivating phosphatase PHLPP1 as a prostate tumor suppressor. We show that Phlpp1-loss causes neoplasia and, upon partial Pten-loss, carcinoma in mouse prostate. This genetic setting initially triggers a growth suppressive response via p53 and the Phlpp2 ortholog, and reveals spontaneous Trp53 inactivation as a condition for full-blown disease. Surprisingly, the co-deletion of PTEN and PHLPP1 in patient samples is highly restricted to metastatic disease and tightly correlated to deletion of TP53 and PHLPP2. These data establish a conceptual framework for progression of PTEN-mutant prostate cancer to life-threatening disease. To better assess the role of Phlpp in prostate we performed micorarray analysis of gene expression in the WT and Pten+/-; Phlpp1-/- mice.磷脂酰肌醇3-激酶（PI 3-Kinase）/AKT通路的过度激活是多种癌症的驱动因素。本研究鉴定出可灭活AKT的磷酸酶PHLPP1为前列腺肿瘤抑制因子。研究显示，Phlpp1缺失会引发小鼠前列腺赘生性病变，而在伴随Pten部分缺失的情况下，会进一步诱发小鼠前列腺癌。该遗传模型最初会通过p53及Phlpp2同源基因触发生长抑制应答，且研究揭示自发性Trp53失活是疾病进展为完全恶性表型的必要条件。令人意外的是，在患者样本中，PTEN与PHLPP1的共缺失仅局限于转移性疾病，且与TP53及PHLPP2的缺失紧密相关。上述研究结果为PTEN突变型前列腺癌进展为致死性疾病构建了概念框架。为更好地评估Phlpp在前列腺病变中的作用，我们对野生型及Pten+/-; Phlpp1-/-小鼠的基因表达开展了micorarray分析。