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

• 批准号: 8260379
• 负责人: Mariangellys Rodriguez
• 金额: $ 3.58万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 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/8260379
• 关键词: Acids; Address; Adult; 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; Cell Survival; Cells; Cessation of life; Clinical Data; Cytochrome P450; Data; Development; Diet; Dietary Fats; ERBB2 gene; 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; 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; expression cloning; fatty acid metabolism; interest; killings; knock-down; lipid metabolism; mRNA Expression; malignant breast neoplasm; novel; overexpression; prevent; protein expression; public health relevance; receptor; research study; treatment strategy; tumor; tumor progression

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(申请人提供)：乳腺癌是美国癌症死亡的第二大原因。成年后荷尔蒙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房上皮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。这个项目的长期目标是了解荷尔蒙信号和生物活性食物成分是如何合作影响乳腺癌的发展的。这项拟议的研究将调查激素信号(特别是IGF1)和膳食脂质(二十碳五烯酸，一种常见于鱼油中的omega-3脂肪酸)在乳腺癌细胞增殖和存活中的作用。需要检验的假设是，在激活的IGF1受体的诱导下，cvtochroP450IAI将二十碳五烯酸代谢成17(18)-环氧二十碳四烯酸，从而促进乳腺癌的增殖和生存。这一假说将在乳腺癌细胞系中作为模型进行验证，使用质谱仪技术测量血脂水平，并使用包括基因敲除、表达克隆和蛋白质印迹在内的分子生物学技术，研究细胞色素P450IAI、IGF1受体(IGF-1R)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。本研究的目的是阐明信号转导途径：A)1GF1/IGF-1R诱导乳腺癌细胞细胞色素P450IAI的表达，B)细胞色素P450IAI促进乳腺癌细胞的增殖和存活，C)17(18)-EPETE促进乳腺癌细胞的增殖和存活。表征这一新的信号通路及其在乳腺癌进展中的作用将促进目前对激素信号和环境因素(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且对健康细胞毒性较小的方式。 公共卫生相关性：该提案支持美国国立卫生研究院预防和治疗乳腺癌的使命。这些研究将填补关于荷尔蒙因素、成年后体重增加和乳腺癌风险增加之间联系的关键知识差距。这些结果将通过表征胰岛素样生长因子调节饮食中omega-3脂肪酸代谢促进乳腺癌生长的生物学机制来推动乳腺癌领域的发展。