Role of IGF-1R in breast cancer proliferation and survival via CYP1A1 epoxygenase

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DESCRIPTION (provided by applicant): Breast cancer is the second leading cause of cancer deaths in the US. The risk of breast cancer is increased by hormonal factors and gain of weight during adulthood. It is known that hormones such as estrogen and insulin-like growth factors (IGF) increase the risk of breast cancer mainly by promoting the growth of breast epithelium. However, the signaling pathway by which hormone factors affect breast cancer has not been elucidated. Regarding weight gain, the biological mechanism by which it affects breast cancer is not understood. The long-term goal of this project is to understand how both hormonal signaling and bioactive food components cooperate to influence the development of breast cancer. The proposed studies will investigate the role of hormone signaling (specifically, IGF1) and the metabolism of a dietary lipid (eicosapentaenoic acid, an omega-3 fatty acid commonly found in fish oil) in the proliferation and survival of breast cancer cells. The hypothesis to be tested is that cvtochrome P450 IAI, induced by activated IGF1 receptor, metabolizes eicosapentaenoic acid into 17(18)-epoxveicosatetraenoic acid, thereby promoting breast cancer proliferation and survival. The hypothesis will be tested in breast cancer cell lines as model using mass spectrometry technology to measure lipid levels and molecular biology techniques, including gene knock down, expression cloning, and western blotting, to study the effects of cytochrome P450 IAI, IGF1 receptor (IGF-1 R), and 17(18)-epoxyeicosatetraenoic acid (17,18-EpETE) in the biology of breast cancer cells. The proposed aims will characterize the signaling pathways by which: A) 1GF1/IGF-1R induces cytochrome P450 IAI expression in breast cancer cells, B) cytochrome P450 IAI promotes the proliferation and survival of breast cancer cells, and C) 17(18)-EpETE enhances the proliferation and survival of breast cancer cells. Characterization of this novel signaling pathway and its role in breast cancer progression will advance the current understanding about how hormone signaling and environmental factors such as diet affect the ability of tumors to grow. The results obtained from this investigation may also lead to targeting the IGF pathway, as a therapeutic approach, in a way that may be more efficient in killing cancer cells and less toxic for healthy cells. PUBLIC HEALTH RELEVANCE: This proposal supports the NIH mission to prevent and treat breast cancer. These studies will close a critical gap in knowledge regarding the link between hormonal factors, weight gain during adulthood, and increased breast cancer risk. The results will advance the breast cancer field by characterizing the biological mechanism by which the metabolism of dietary omega-3 fatty acids is regulated by insulin-like growth factors to promote the growth of breast cancer.