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Validation of SHIP2 as a Novel Molecular Target in Obesity-Linked Cancer’
Tumor Cell Biology II
We propose to delineate the molecular mechanisms underlying obesity-related cancer risk by studying the signaling cross-talk between insulin and leptin, two important regulators of satiety and obesity. Here we focus on the role of a 5’- inositol phosphatase SHIP2 in this proposed cross-talk. SHIP2 is induced by a high-fat diet and obesity. Overexpression of SHIP2 causes insulin resistance and genetic knockout of SHIP2 in mice prevents obesity induced by a high-fat diet. In addition to its role in insulin signaling, SHIP2 regulates cell adhesion/migration and receptor endocytosis. Our preliminary work shows high levels of SHIP2 protein in many types of cancer cells including breast epithelial cells. Furthermore, leptin, a hormone elevated during obesity, up-regulates SHIP2 in MCF-7 breast cancer cells and RNA interference-mediated silencing of SHIP2 in MCF-7 cells decreases cell proliferation and leptin-induced cell migration. We propose that SHIP2 is the missing link between high-fat diet/obesity/insulin resistance and subsequent cancer development. We will test the hypothesis that SHIP2 plays a positive role in cancers associated with obesity by mediating and/or regulating leptin-insulin signaling cross-talk . We will employ a combination of in vitro (MCF-7 and MCF-10A human mammary cells) and in vivo (a diet-induced obese rat model of breast cancer) approaches to methodically evaluate the role of SHIP2 in obesity-induced cancer risk. Two specific Aims are developed for this purpose: 1. Determine the role of SHIP2 in leptin signaling and in leptin receptor endocytosis/degradation. 2. Determine the role of SHIP2 for oncogenic transformation (a) in vitro using MCF-7 mammary carcinoma cells and MCF-10A immortalized mammary epithelial cells; and (b) in vivo using a diet-induced obese rat model of breast cancer. Significance: Obesity is an important risk factor for increased incidence and metastasis of breast cancer. Signaling cross-talk among hormones important to metabolism and mammary gland function may play a key role in this complication of obesity. We predict that SHIP2, a regulator of insulin signaling and possibly that of leptin, will mediate such a cross-talk between insulin and leptin, thereby linking obesity and cancer. Our studies described in this proposal will validate SHIP2 as a unique drug target amenable for therapeutic intervention that could curb the development of cancer and restore normal insulin signaling during obesity.
Obesity is an important risk factor for the development of breast cancer. Better understanding of the molecular mechanisms underlying this predisposition is urgently needed to design novel preventive and targeted therapeutic approaches. This proposal specifically aims to study the mechanisms of obesity-induced cancer predisposition at the cell and molecular- as well as the whole-animal level. The focus of this investigation is a 5’-inositol phosphatase termed SHIP2, a known inhibitor of insulin function. SHIP2 levels in skeletal muscle cells are increased by a high-fat diet and obesity and genetic deletion of SHIP2 prevents obesity induced by high-fat diet. SHIP2 is also present in high levels in many types of cancer cells. In some types of cancer cells SHIP2 regulates cell adhesion, cell spreading and receptor trafficking. Based on these evidences, we hypothesize that SHIP2 plays an active role in the development of obesity-associated cancer risk following its up-regulation by high-fat diet/obesity. Obesity is characterized by elevated serum levels of the adipocyte-secreted hormone leptin, a major regulator of satiety and fat deposition. Leptin stimulates breast cancer cell proliferation and migration and is an important determinant of mammary tumorigenesis. As leptin and insulin activate many of the same signaling intermediates, a potential role of SHIP2 in leptin signaling is proposed here. Studies are designed to examine the possible role for SHIP2 in leptin signaling. We will employ a combination of in vitro (normal and cancerous breast cells) and in vivo (a diet-induced obese rat model of breast cancer) approaches to methodically evaluate the role of SHIP2 in obesity-induced cancer risk. We will determine: 1) whether SHIP2 regulates leptin signaling; 2) whether SHIP2 mediates leptin affects on cell proliferation and migration; and 3) whether SHIP2 over-expression is necessary and/or sufficient to induce transformation of normal cells into cancer cells. The identification of SHIP2 as a key molecule in leptin signaling and the characterization of its role in obesity-associated cancer development will make a significant contribution to our understanding of cross-talk between insulin, leptin and growth factor signaling during breast cancer development. SHIP2 is an attractive ‘drugable’ target, inhibition of which could potentially restore impaired insulin signaling as well as prevent cancer development in high-risk obese individuals .