Chen, M. H., Pratt, C. P., Zeeman, M. E., Schultz, N., Taylor, B. S., O'Neill, A., Castillo-Martin, M., Nowak, D. G., Naguib, A., Grace, D. M., Murn, J., Navin, N., Atwal, G. S., Sander, C., Gerald, W. L., Cordon-Cardo, C., Newton, A. C., Carver, B. S., Trotman, L. C. (August 2011) Identification of PHLPP1 as a Tumor Suppressor Reveals the Role of Feedback Activation in PTEN-Mutant Prostate Cancer Progression. Cancer Cell, 20 (2). pp. 173-186. ISSN 1535-6108
Abstract
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.
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