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

被引：145

作者：

Chen, Muhan ^{[1
]}

Pratt, Christopher P. ^{[1
]}

Zeeman, Martha E. ^{[1
]}

Schultz, Nikolaus ^{[2
]}

Taylor, Barry S. ^{[2
]}

O'Neill, Audrey ^{[3
]}

Castillo-Martin, Mireia ^{[4
]}

Nowak, Dawid G. ^{[1
]}

Naguib, Adam ^{[1
]}

Grace, Danielle M. ^{[1
]}

Murn, Jernej ^{[1
]}

Navin, Nick ^{[5
]}

Atwal, Gurinder S. ^{[1
]}

Sander, Chris ^{[2
]}

Gerald, William L. ^{[6
]}

Cordon-Cardo, Carlos ^{[4
]}

Newton, Alexandra C. ^{[3
]}

Carver, Brett S. ^{[7
]}

Trotman, Lloyd C. ^{[1
]}

机构：

[1] Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA

[2] Mem Sloan Kettering Canc Ctr, Computat Biol Program, New York, NY 10021 USA

[3] Univ Calif San Diego, Dept Pharmacol, La Jolla, CA 92093 USA

[4] Columbia Univ, Dept Pathol, New York, NY 10032 USA

[5] Univ Texas MD Anderson Canc Ctr, Dept Genet, Dept Bioinformat & Computat Biol, Houston, TX 77030 USA

[6] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, Dept Pathol, New York, NY 10021 USA

[7] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, Div Urol, Dept Surg, New York, NY 10021 USA

来源：

CANCER CELL | 2011年 / 20卷 / 02期

关键词：

MTOR COMPLEX; MICE; AKT; PHOSPHATASE; SENESCENCE; PATHWAY; PROTEIN; GROWTH; DEPHOSPHORYLATES; TUMORIGENESIS;

D O I：

10.1016/j.ccr.2011.07.013

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：173 / 186

页数：14

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