Molecular targets of soy isoflavones in breast cancer progression

大豆异黄酮在乳腺癌进展中的分子靶标

基本信息

批准号：
8133781
负责人：
SURANGANIE DHARMAWARDHANE
金额：
$ 11.14万
依托单位：
UNIVERSITY OF PUERTO RICO MED SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-10 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8133781
关键词：
Address Affect Angiogenesis Inhibitors Antibodies Antioxidants Binding Biological Assay Breast Cancer Cell Cancer Patient Cancer cell line Cells Consumption Custom Data Development Dietary Phytochemical Disease Distant Metastasis Estrogen Antagonists Estrogen Receptor beta Estrogen Receptors Estrogens Experimental Designs Fatty acid glycerol esters Focal Adhesion Kinase 1 Genistein Genomics Goals Green Fluorescent Proteins Growth Factor Receptors Guidelines Image Analysis In Situ In Vitro Integrins Knowledge Laboratories Literature Malignant - descriptor Malignant Neoplasms Mammary Neoplasms Mammary gland Mediating Methods Microarray Analysis Molecular Target Mus Neoplasm Metastasis Nude Mice Phosphorylation Phytochemical Post-Translational Protein Processing Prevention Preventive Primary Neoplasm Property Protein Isoforms Proteins Proteomics Public Health Publishing Receptor Signaling Relative (related person)Research Risk Role Signal Pathway Signal Transduction Signaling Molecule Soy Foods Survivors Technology Testing Time Tissue-Specific Gene Expression Transducers Western Blotting Woman base breast tumorigenesis cancer cell cancer initiation carcinogenesis cell motility daidzein dietary constituent glycitein in vivo innovation malignant breast neoplasm mouse model polyphenol prevent promoter receptor expression response soy soy protein isolate therapeutic target tissue culture tumor tumor growth tumor progression

项目摘要

DESCRIPTION (provided by applicant): The OBJECTIVE of this proposal is to investigate the role of soy phytochemicals, dietary constituents with known cancer-preventive properties, in breast cancer metastasis. The RATIONALE is that soy isoflavones can affect cancer progression by antioxidant, estrogenic/antiestrogenic, antiangiogenic, and other inhibitory mechanisms. Most studies on the role of soy compounds in cancer focus on cancer initiation and not progression. This proposal addresses a GAP IN KNOWLEDGE concerning the molecular targets of the major soy isoflavones genistein and dadizein in breast cancer metastasis, the most deadly aspect of the disease. We have shown that the activity of a key signaling intermediate of cancer cell invasion, focal adhesion kinase (FAK), is regulated by genistein and daidzein in metastatic breast cancer cells. Preliminary data using human breast cancer cells in tissue culture and a nude mouse model of experimental metastasis demonstrate that genistein decreases while daidzein increases metastatic breast cancer cell migration, mammary tumor growth, and metastasis. Our HYPOTHESIS is that genistein prevents while daidzein promotes metastatic breast cancer progression. These differential effects are dependent on the myriad of FAK-mediated signaling cascades. The STUDY DESIGN will use innovative in situ image analysis and genomic and proteomic microarray technology to elucidate the FAK signaling pathways that are regulated differentially by soy isoflavones in metastatic breast cancer cell lines that do not express estrogen receptors (ER), only ER beta or both ER isoforms. AIM 1 will delineate molecular targets of genistein, daidzein, and combined soy isoflavones on metastatic breast cancer cells in vitro. AIM 2 will delineate molecular targets of genistein, daidzein, and combined soy isoflavones on mammary tumors, distant metastases, and invasive breast cancer cells in vivo. The proposed comprehensive-analysis is expected to identify signaling molecules regulated by soy compounds relevant for breast cancer progression. This timely research is SIGNIFICANT to public health by advancing the understanding of the role of natural dietary compounds from soy foods in breast cancer. The proposed elucidation of the specific molecular targets of soy isoflavones will enable targeted therapeutic strategies for metastatic breast cancer. Our broad-range goal is to impact the development of dietary guidelines for women at risk for breast cancer, breast cancer patients, and survivors.

描述（由申请人提供）：该提案的目的是研究大豆植物化学物质（具有已知防癌特性的膳食成分）在乳腺癌转移中的作用。基本原理是大豆异黄酮可以通过抗氧化、雌激素/抗雌激素、抗血管生成和其他抑制机制影响癌症进展。大多数关于大豆化合物在癌症中的作用的研究都集中在癌症的发生而不是进展上。该提案解决了有关主要大豆异黄酮金雀异黄酮和达地黄在乳腺癌转移（该疾病最致命的方面）中的分子靶标的知识差距。我们已经证明，癌细胞侵袭的关键信号中间体——粘着斑激酶（FAK）的活性受到转移性乳腺癌细胞中金雀异黄素和大豆黄酮的调节。使用组织培养中的人乳腺癌细胞和实验性转移的裸鼠模型获得的初步数据表明，金雀异黄素减少，而大豆黄酮增加转移性乳腺癌细胞的迁移、乳腺肿瘤生长和转移。我们的假设是金雀异黄素可以预防转移性乳腺癌，而大豆黄酮则可以促进转移性乳腺癌的进展。这些差异效应取决于无数 FAK 介导的信号级联。研究设计将使用创新的原位图像分析以及基因组和蛋白质组微阵列技术来阐明在不表达雌激素受体（ER）、仅表达ERβ或两者的转移性乳腺癌细胞系中大豆异黄酮差异调节的FAK信号通路ER亚型。 AIM 1 将在体外描绘金雀异黄酮、大豆黄酮和组合大豆异黄酮对转移性乳腺癌细胞的分子靶标。 AIM 2 将描绘金雀花素、大豆黄酮和组合大豆异黄酮对体内乳腺肿瘤、远处转移和侵袭性乳腺癌细胞的分子靶点。所提出的综合分析预计将鉴定出与乳腺癌进展相关的大豆化合物调节的信号分子。这项及时的研究对公众健康具有重要意义，它可以增进人们对大豆食品中天然膳食化合物在乳腺癌中作用的了解。对大豆异黄酮特定分子靶点的阐明将为转移性乳腺癌的靶向治疗策略提供支持。我们的广泛目标是影响乳腺癌风险女性、乳腺癌患者和幸存者饮食指南的制定。