Leptin receptor is necessary for pluripotency of breast cancer cells. Leptin is a hormone primarily secreted by fat cells. Leptin receptor (LepR) is a cytokine receptor expressed in both the brain, periphery, and multiple tumors. Our recently published data indicate that LepR is expressed in breast cancer subpopulations of tumor-initiating cells; that leptin is necessary for tumor formation in orthotopic transplants; and that it is required for self-renewal of tumor-initiating cells. Our mechanistic studies, in both mouse and human mammary cancer cells, indicate that leptin and LepR are necessary for NANOG expression. NANOG is a master regulator of self-renewal in normal stem cells and recent studies indicate that NANOG also regulates self-renewal of CSCs in primary tumors. We are now studying the mechanics of LepR regulation of cancer stem cell self-renewal.
Syndecan-3 regulates hypothalamic circuits necessary for maintenance of body weight. A second research focus is on the function of syndecan-3, a protein that we showed controls body weight and important in development of obesity on diets high in fat much like the "American Western" type diet. Syndecans are a family of proteins on the surface of cells that act as molecular "flypaper," helping proteins attach to cells and also helping cells attach to one another. We recently published that syndecan-3 regulates the key hypothalamic circuits necessary for balancing food intake and energy expenditure.
Obesity increases the risk of developing multiple health problems including diabetes, heart disease, and cancer. Despite public awareness regarding the serious health consequence of excess fat, obesity continues to increase in developed and developing nations. To understand how obesity occurs and how it may be treated requires an understanding of the genes that regulate body weight and how their function is influenced by environmental factors such as diets high in calories and dietary fat. Our research focuses on hypothalamic mechanisms necessary for regulating body weight and second the role of the adipocyte hormone leptin in promoting breast cancer.
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Zheng, Q., Zhu, J., Shanabrough, M., Borok, E., Benoit, S.C., Horvath, T.L., Clegg, D.J., and Reizes, O. Enhanced Anorexigenic signaling in lean obesity resistant syndecan-3 null mice. Neuroscience 2010, 171: 1032-1040.
Zheng, Q., Dunlap, S.M., Zhu, J., Downs-Kelly, E., Rich, J.N., Hursting, S.D., Berger, N.A., and Reizes, O. Leptin deficiency suppresses MMTV-Wnt-1 mammary tumor growth and abrogates tumor initiating cell survival. Endocr Relat Cancer 2011, 18: 491-503. (PMCID: 3197719). Accompanying Editorial Commentary by Park, J. and Scherer, P.E. Leptin and cancer: from cancer stem cells to metastasis.