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Inhibition of Leptin Signaling for Treatment of Breast Cancer
Mammary tumors (MT) over-express leptin and its receptor (OB-R) and their levels correlate with metastasis and lower patient survival. Obesity and menopause characterized by high leptin levels are related to the incidence of MT. Mutant mice lacking leptin signaling have low incidence of MT. Progeny from mice genetically engineered to develop MT do not develop them when crossed with leptin deficient mutant mice. Estradiol induces proliferation of breast cancer cells expressing the estradiol receptor (ER+). Leptin signaling induces aromatase activity and ER transactivation that potentates estradiol effects on responsive tumors. We have found that leptin increases the levels of inflammatory cytokines, angiogenic factors and their receptors (IL-1, LIF and VEGF) and b3 integrin in human endometrial cancer cells. These effects can be blocked by leptin peptide antagonists (LPAs), a group of novel, non-toxic and potent inhibitors of leptin/OB-R signaling that we have developed in our laboratory. LPAs decrease the leptin-dependent levels of cytokines and angiogenic factors and their receptors in human endometrial cancer cells in vitro. LPAs block leptin-induced effects on mouse embryo implantation and reduce the levels of VEGF, LIF and IL-1 receptors and b3 integrin. Moreover, LPAs also inhibit leptin-induced proliferation, adhesion and migration of endometrial and mammary cancer cells (from human and mouse). We hypothesize that leptin signaling contributes to the adhesive, mitogenic, invasive and angiogenic qualities of malignant mammary cells. Hence, disruption of leptin/OB-R signaling should prevent the establishment of mammary tumors or reduce the size of lesions and/or their metastasis in already established tumors. LPAs may improve the efficacy of chemotherapeutic regimens. To test this hypothesis we will use LPAs to inhibit leptin signaling in mouse models (immunocompromised, immunocompetent and transgenic mice). Specifically, we propose to determine if LPA disruption of leptin signaling will inhibit establishment and/or growth of MCF-7 (ER+) and/or MDA-MB 231 (ER-) human breast cancer cells and 4T1 mouse malignant mammary cells in immunocompromised and immunocompetent mouse models, respectively. We will aim to also determine if disruption of leptin signaling is sufficient for a reduction in the establishment and/or growth of tumors in transgenic mice engineered for mammary tumor (MMTV/TFG-a). The information yielded from these studies could lead to the development of novel therapies for clinical management of breast cancer.
Although primarily known for its roles in obesity and reproduction, the protein leptin has recently been implicated in breast cancer where it appears to promote both proliferation of cancer cells and angiogenesis, the formation of new blood vessels necessary for tumor growth. Malignant mammary tumors that secrete high levels of leptin exhibit higher incidence of metastasis and lower survival. Increased leptin levels which accompany obesity and menopause increase the risk for development of breast cancer. Mutant mice with impaired leptin function do not develop mammary tumors. Although the specific role of leptin in breast cancer is not completely understood, there is compelling evidence that blocking leptin’s biological activity (signaling) could be a novel approach to treat breast cancer. We have recently designed and tested novel and non-toxic inhibitors of leptin signaling that we have called leptin peptide antagonists (LPAs). We have demonstrated that these LPAs block leptin-induced proliferation, adhesion and invasion of endometrial and mammary cancer cells grown in tissue culture by interfering with the ability of leptin to regulate several key molecular factors involved in the process of tumor growth and metastasis. We hypothesize that leptin contributes to the adhesive, proliferative, invasive and angiogenic qualities of mammary malignant cells. Hence, disruption of leptin signaling should prevent the establishment of mammary tumors or the growth and spread of already established tumors. To test this hypothesis we propose to block leptin with LPAs to determine if disruption of leptin signaling is sufficient for a reduction in the establishment and/or growth of human and mouse mammary cancer cells in mice. In spite of the mounting evidence that leptin is a factor in tumor development, this proposed study represents the first time that a therapeutic agent developed to target leptin signaling will be tested to treat breast cancer.