Molecular targets of soy isoflavones in breast cancer progression

描述（由申请人提供）：本提案的目的是研究大豆植物化学物质，具有已知癌症预防特性的膳食成分，在乳腺癌转移中的作用。其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的进展。大多数关于大豆化合物在癌症中的作用的研究集中在癌症的发生而不是进展。该建议解决了关于主要大豆异黄酮染料木素和大豆黄酮在乳腺癌转移中的分子靶点的知识差距，这是该疾病最致命的方面。我们已经证明转移性乳腺癌细胞中癌细胞侵袭的关键信号介质，局灶黏附激酶（FAK）的活性受到染料木素和大豆苷元的调节。对人乳腺癌细胞进行组织培养和裸鼠实验转移模型的初步数据表明，染料木素减少了转移性乳腺癌细胞的迁移，而大豆苷元增加了转移性乳腺癌细胞的迁移、乳腺肿瘤的生长和转移。我们的假设是染料木素可以预防乳腺癌的转移性进展，而大豆黄酮可以促进乳腺癌的转移性进展。这些不同的影响取决于无数的fak介导的信号级联反应。研究设计将使用创新的原位图像分析和基因组学和蛋白质组学微阵列技术来阐明在不表达雌激素受体（ER）、仅表达ER β或两种ER亚型的转移性乳腺癌细胞系中受大豆异黄酮差异调节的FAK信号通路。AIM 1将描述染料木素、大豆黄酮和联合大豆异黄酮对转移性乳腺癌细胞的体外分子靶点。AIM 2将描述染料木素、大豆黄酮和联合大豆异黄酮在乳腺肿瘤、远处转移和浸润性乳腺癌细胞中的分子靶点。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，它促进了人们对来自大豆食品的天然膳食化合物在乳腺癌中的作用的理解。大豆异黄酮的特异性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。我们广泛的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。

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.