Phosphoinositol phosphatase SHIP2 promotes cancer development and metastasis coupled with alterations in EGF receptor turnover

Nagendra K. Prasad, Manish Tandon, Sunil Badve, Paul W. Snyder, Harikrishna Nakshatri

Research output: Contribution to journalArticle

58 Citations (Scopus)

Abstract

Phosphoinositol phosphatases are important regulators of signaling pathways relevant to both diabetes and cancer. A 3′-phosphoinositol phosphatase, phosphatase homologous to tensin (PTEN), is both a tumor suppressor and a negative regulator of insulin action. A 5′-phosphoinositol phosphatase, SH2-containing 5′-inositol 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 epidermal growth factor receptor (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 with non-cancerous breast tissues contain elevated expression of SHIP2 protein. Taken together, our results demonstrate that SHIP2 is a clinically relevant novel anticancer target that links perturbed metabolism to cancer development.

Original languageEnglish
Pages (from-to)25-34
Number of pages10
JournalCarcinogenesis
Volume29
Issue number1
DOIs
StatePublished - Jan 2008

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Phosphoric Monoester Hydrolases
Epidermal Growth Factor Receptor
Neoplasm Metastasis
Neoplasms
Breast Neoplasms
PTEN Phosphohydrolase
Insulin
High Fat Diet
Drug Delivery Systems
RNA Interference
Endocytosis
Cytoskeleton
Nude Mice
Breast
Obesity
Cell Proliferation
Cell Line
Proteins

ASJC Scopus subject areas

  • Cancer Research

Cite this

Phosphoinositol phosphatase SHIP2 promotes cancer development and metastasis coupled with alterations in EGF receptor turnover. / Prasad, Nagendra K.; Tandon, Manish; Badve, Sunil; Snyder, Paul W.; Nakshatri, Harikrishna.

In: Carcinogenesis, Vol. 29, No. 1, 01.2008, p. 25-34.

Research output: Contribution to journalArticle

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