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

描述（由申请人提供）：乳腺癌是美国癌症死亡的第二大原因。乳腺癌的风险增加激素因素和体重增加在成年期。众所周知，激素如雌激素和胰岛素样生长因子（IGF）主要通过促进乳腺上皮细胞的生长来增加乳腺癌的风险。然而，激素因子影响乳腺癌的信号通路尚未阐明。关于体重增加，它影响乳腺癌的生物学机制尚不清楚。该项目的长期目标是了解激素信号和生物活性食物成分如何合作影响乳腺癌的发展。拟议的研究将调查激素信号（特别是IGF 1）和饮食脂质（二十碳五烯酸，鱼油中常见的ω-3脂肪酸）代谢在乳腺癌细胞增殖和存活中的作用。待检验的假设是，由激活的IGF 1受体诱导的细胞色素P450 IAI将二十碳五烯酸代谢为17（18）-环氧二十碳四烯酸，从而促进乳腺癌增殖和存活。该假设将在乳腺癌细胞系中作为模型进行测试，使用质谱技术测量脂质水平和分子生物学技术，包括基因敲除、表达克隆和蛋白质印迹，以研究细胞色素P450 IAI、IGF 1受体（IGF-1 R）和17（18）-环氧二十碳四烯酸（17，18-EpETE）在乳腺癌细胞生物学中的作用。提出的目的将表征信号通路，通过该信号通路：A）1GF 1/IGF-1 R诱导乳腺癌细胞中细胞色素P450 IAI表达，B）细胞色素P450 IAI促进乳腺癌细胞的增殖和存活，以及C）17（18）-EpETE增强乳腺癌细胞的增殖和存活。对这种新型信号通路及其在乳腺癌进展中的作用的表征将推进目前对激素信号传导和环境因素（如饮食）如何影响肿瘤生长能力的理解。从这项研究中获得的结果也可能导致靶向IGF途径，作为一种治疗方法，以一种可能更有效地杀死癌细胞和对健康细胞毒性较小的方式。 公共卫生相关性：该提案支持NIH预防和治疗乳腺癌的使命。这些研究将填补有关激素因素，成年期体重增加和乳腺癌风险增加之间联系的知识空白。这些结果将通过表征膳食omega-3脂肪酸代谢受胰岛素样生长因子调节以促进乳腺癌生长的生物学机制来推进乳腺癌领域。

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.