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

IGF-1R 通过 CYP1A1 环氧化酶在乳腺癌增殖和生存中的作用

基本信息

批准号：
7802543
负责人：
Mariangellys Rodriguez
金额：
$ 3.48万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-05-01 至 2013-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7802543
关键词：
Acids Address Affect Apoptotic Aromatic Polycyclic Hydrocarbons Biochemical Biological Biology Body Weight Changes Breast Breast Cancer Cell Breast Carcinoma CYP1A1 gene Cancer Etiology Cancer cell line Carcinogens Cell Line Cell Proliferation Cells Cessation of life Clinical Data Cytochrome P450 Data Development Diet Dietary Fats Eicosapentaenoic Acid Environmental Risk Factor Epithelial Cells Epithelium Estrogen Receptor Status Estrogen receptor negative Estrogen receptor positive Estrogens Etiology Fish Oils Genes Genetic Goals Growth Hormonal Hormones IGF1 gene IRS1 gene In Vitro Insulin-Like Growth Factor I Insulin-Like-Growth Factor I Receptor Investigation Knowledge Lead Ligands Link Lipids MAP Kinase Gene MCF7 cell Malignant Neoplasms Mammary gland Mass Spectrum Analysis Measures Messenger RNA Metabolism Methods Mission Modeling Molecular Biology Techniques Monitor Obesity Omega-3 Fatty Acids PI3K/AKT Pathway interactions Premenopause Preventive Production Progesterone Receptors Protein Tyrosine Kinase Risk Role SKBR3 Serum Signal Pathway Signal Transduction Somatomedins Starvation Stress T47D Technology Testing The Sun Therapeutic United States National Institutes of Health Weight Gain Western Blotting Woman base bioactive food component cancer cell cancer prevention cancer risk cancer therapy cell transformation expression cloning fatty acid metabolism interest killings knock-down lipid metabolism malignant breast neoplasm novel overexpression prevent protein expression public health relevance receptor research study treatment strategy tumor tumor progression

项目摘要

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.

描述（由申请人提供）：乳腺癌是美国癌症死亡的第二大原因。成年期间的激素因素和体重增加会增加患乳腺癌的风险。众所周知，雌激素和胰岛素样生长因子（IGF）等激素主要通过促进乳腺上皮的生长来增加患乳腺癌的风险。然而，激素因素影响乳腺癌的信号通路尚未阐明。关于体重增加，其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传导和生物活性食物成分如何协同影响乳腺癌的发展。拟议的研究将调查激素信号传导（特别是 IGF1）和膳食脂质（二十碳五烯酸，鱼油中常见的 omega-3 脂肪酸）的代谢在乳腺癌细胞增殖和存活中的作用。待测试的假设是，由激活的IGF1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进行测试，作为模型，使用质谱技术测量脂质水平，并使用分子生物学技术（包括基因敲除、表达克隆和蛋白质印迹）来研究细胞色素 P450 IAI、IGF1 受体（IGF1）的影响。 -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应用。拟议的目标将表征信号传导途径：A) 1GF1/IGF-1R 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。这种新型信号通路的表征及其在乳腺癌进展中的作用将促进目前对激素信号传导和饮食等环境因素如何影响肿瘤生长能力的理解。这项研究获得的结果还可能导致以 IGF 途径为目标的治疗方法，这种治疗方法可能更有效地杀死癌细胞，并且对健康细胞的毒性更小。公共卫生相关性：该提案支持 NIH 预防和治疗乳腺癌的使命。这些研究将弥补关于激素因素、成年期体重增加和乳腺癌风险增加之间联系的关键知识空白。该研究结果将通过表征胰岛素样生长因子调节膳食 omega-3 脂肪酸代谢以促进乳腺癌生长的生物学机制，从而推动乳腺癌领域的发展。