Author/Authors :
Chen، نويسنده , , Muhan and Pratt، نويسنده , , Christopher P. and Zeeman، نويسنده , , Martha E. and Schultz، نويسنده , , Nikolaus and Taylor، نويسنده , , Barry S. and OʹNeill، نويسنده , , Audrey and Castillo-Martin، نويسنده , , Mireia and Nowak، نويسنده , , Dawid G. and Naguib، نويسنده , , Adam and Grace، نويسنده , , Danielle M. and Murn، نويسنده , , Jernej and Navin، نويسنده , , Nick and Atwal، نويسنده , , Gurinder S. and Sander، نويسنده , , Chris and Gerald، نويسنده , , William L. and Cordon-Cardo، نويسنده , , Carlos and Newton، نويسنده , , Alexandra C. and Carver، نويسنده , , Brett S. and Trotman، نويسنده , , Lloyd C.، نويسنده ,
Abstract :
Summary
ctivation 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.
