Details

Autor(en) / Beteiligte

• Chen, Muhan
• Pratt, Christopher P.
• Zeeman, Martha E.
• Schultz, Nikolaus
• Taylor, Barry S.
• O'Neill, Audrey
• Castillo-Martin, Mireia
• Nowak, Dawid G.
• Naguib, Adam
• Grace, Danielle M.
• Murn, Jernej
• Navin, Nick
• Atwal, Gurinder S.
• Sander, Chris
• Gerald, William L.
• Cordon-Cardo, Carlos
• Newton, Alexandra C.
• Carver, Brett S.
• Trotman, Lloyd C.

Titel

Identification of PHLPP1 as a Tumor Suppressor Reveals the Role of Feedback Activation in PTEN-Mutant Prostate Cancer Progression

Ist Teil von

• Cancer cell, 2011-08, Vol.20 (2), p.173-186

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2011

Quelle

Access via ScienceDirect (Elsevier)

Beschreibungen/Notizen

• 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. ► PHLPP1 is a prostate tumor suppressor that cooperates with PTEN ► Phlpp1/Pten codeletion requires p53 inactivation for senescence bypass ► Codeletion is associated with metastatic disease ► Codeletion triggers rapamycin-sensitive p53 and Phlpp2 activation