Carcinogenesis Advance Access first published online on September 24, 2007
This version published online on October 4, 2007
Carcinogenesis, doi:10.1093/carcin/bgm213
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PHOSPHOINOSITOL PHOSPHATASE SHIP2 PROMOTES CANCER DEVELOPMENT AND METASTASIS COUPLED WITH ALTERATIONS IN EGF RECEPTOR TURNOVER
1 From the department of Basic Medical Sciences and Purdue Cancer Center, Purdue University, West Lafayette, IN, USA
2 From the department of Pathology and Laboratory Medicine, School of Medicine, Indiana University Purdue University Indianapolis, IN, USA
3 From the department of Comparative Pathobiology, Purdue University, West Lafayette, IN, USA
4 From the department of Surgery, Biochemistry and Molecular Biology and Walther Oncology Center, Indiana University School of Medicine, Indianapolis, IN, USA
* Address correspondence to: Dr. Nagendra K. Prasad, Department of Basic Medical Sciences, LYNN Hall, Purdue University, 625 Harrison Street, West Lafayette, Indiana 47907, Tel: 765-494-4717, Fax: 765-494-0781, E-mail: nprasad{at}purdue.edu
Phosphoinositol phosphatases are important regulators of signaling pathways relevant to both diabetes and cancer. A 3'-phosphoinositol phosphatase, PTEN is both a tumor suppressor and a negative regulator of insulin action. A 5'-phosphoinositol phosphatase, SHIP2 regulates insulin signaling and its genetic knockout prevents high-fat-diet-induced obesity in mice. SHIP2 also regulates cytoskeleton remodeling and receptor endocytosis. This and the fact that both PTEN and SHIP2 act on the same substrate suggest a potential role for SHIP2 in cancer. Here we report that, in direct contrast to PTEN, SHIP2 protein expression is elevated in a number of breast cancer cell lines. RNA interference-mediated silencing of SHIP2 in MDA-231 cells suppresses EGFR levels by means of enhanced receptor degradation. Furthermore, endogenous SHIP2 in MDA-231 breast cancer cells supports in vitro cell proliferation, increases cellular sensitivity to drugs targeting the EGFR and supports cancer development and metastasis in nude mice. In addition, significantly high proportions (44%; P = 0.0001) of clinical specimens of breast cancer tissues in comparison to non-cancerous breast tissues contain elevated expression of SHIP2 protein. Taken together, our results demonstrate that SHIP2 is a clinically relevant novel anti-cancer target that links perturbed metabolism to cancer development.
‘The order of figures 4 and 5 has been corrected.’
Received May 4, 2007; revised September 10, 2007; accepted September 15, 2007.