Molecular targets of soy isoflavones in breast cancer progression

描述(申请人提供)：这项提案的目的是调查大豆植物化学物质在乳腺癌转移中的作用，大豆植物化学物质是已知的防癌特性的饮食成分。其基本原理是，大豆异黄酮可以通过抗氧化剂、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。这项建议解决了关于主要大豆异黄酮染料木素和大豆黄素在乳腺癌转移中的分子靶点的知识空白，乳腺癌转移是乳腺癌最致命的方面。我们已经证明，在转移性乳腺癌细胞中，粘着斑激酶(FAK)是癌细胞侵袭的关键信号中间产物，其活性受到染料木素和大豆苷元的调节。使用组织培养的人乳腺癌细胞和裸鼠实验转移模型的初步数据显示，染料木素减少，而大豆苷元增加转移的乳腺癌细胞迁移，乳腺肿瘤生长和转移。我们的假设是金雀异黄素预防而大豆苷元促进转移性乳腺癌进展。这些不同的效应依赖于FAK介导的无数信号级联。这项研究设计将使用创新的原位图像分析和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或同时表达ERβ和ER亚型的转移性乳腺癌细胞系中，受大豆异黄酮差异调控的FAK信号通路。目的1研究染料木素、大豆苷元和大豆异黄酮类化合物在体外对转移性乳腺癌细胞的作用。目的2将描绘染料木素、大豆苷元和结合大豆异黄酮体内对乳腺肿瘤、远处转移和浸润性乳腺癌细胞的分子靶点。这项拟议的综合分析有望确定与乳腺癌进展相关的大豆化合物调控的信号分子。这项及时的研究对公众健康具有重要意义，因为它促进了人们对大豆食品中天然饮食化合物在乳腺癌中的作用的理解。大豆异黄酮类特定分子靶点的阐明将使转移性乳腺癌的靶向治疗策略成为可能。我们的广泛目标是影响乳腺癌高危女性、乳腺癌患者和幸存者饮食指南的制定。

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.