Identification of PHLPP1 as a Tumor Suppressor Reveals the Role of Feedback Activation in PTEN-Mutant Prostate Cancer Progression
Menée à l'aide d'un modèle murin, cette étude montre que le gène de la phosphatase PHLPP1 joue un rôle de suppresseur de tumeurs, en coopération avec PTEN, dans le cancer de la prostate
Hyperactivation 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, on 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 codeletion 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. º PHLPP1 is a prostate tumor suppressor that cooperates with PTEN º Phlpp1/Pten codeletion requires p53 inactivation for senescence bypass º Codeletion is associated with metastatic disease º Codeletion triggers rapamycin-sensitive p53 and Phlpp2 activation