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点

基本信息

批准号：
9249605
负责人：
SURANGANIE DHARMAWARDHANE
金额：
$ 11.25万
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 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9249605
关键词：
Address Adjuvant Therapy Affect Award Bacteria Blood Circulation Breast Cancer Cell Breast Cancer Patient Breast Cancer cell line Cancer Cell Growth Cancer Control Cancer Patient Cancer Prognosis Cancer Survivor Cancer cell line Carcinogens Carcinoma Cause of Death Cell Cycle Progression Cell Proliferation Cell Survival Cell physiology Chemicals Consumption Data Diagnosis Diet Dietary Factors Disease Disseminated Malignant Neoplasm Distant ERBB2 gene Early Diagnosis Environmental Risk Factor Estrogen receptor positive Gene Expression Gene Proteins Genistein Goals Growth Factor Receptors Human Immunocompromised Host In Vitro Individual Internal Ribosome Entry Site Intestines Investigation Isoflavones Knowledge Liver Lung Malignant Neoplasms Mammary Neoplasms Mediating Metastatic Neoplasm to the Lung Metastatic breast cancer Metastatic/Recurrent Mission Modeling Molecular Molecular Target Mus National Institute of General Medical Sciences Neoplasm Metastasis Nude Mice Nutrient Organ Patients Peptide Initiation Factors Primary Neoplasm Protein Biosynthesis Public Health Publishing Recommendation Regulation Reporting Research Risk Role Signal Transduction Sirolimus Site Small Interfering RNA Solid Neoplasm Soy Foods Stress Survival Rate Survivors Testing Therapeutic Time Up-Regulation Work angiogenesis base bone c-myc Genes cancer cell cancer prevention cancer type daidzein equol glycitein gut microbiota improved in vivo knock-down mRNA Expression malignant breast neoplasm migration mouse model neoplastic cell prevent protein expression public health relevance response soy soy protein isolate transcription factor tumor tumor growth tumor progression tumorigenesis vector control

项目摘要

DESCRIPTION (provided by applicant): The broad, long-term objective of this proposal is to elucidate the effects of soy foods on metastatic cancers. Metastatic cancer cells in primary tumors, or in the circulation, may establish secondary metastases at distant sites via a plethora of triggers, including dietary and environmental factors. Much work has been conducted on dietary soy in cancer prevention, but not in metastasis of established cancers. Therefore, this proposal addresses a gap in knowledge concerning the role and molecular targets of the major soy isoflavones in metastatic breast cancer. The rationale comes from data generated during the previous SC3 award. We reported that dietary administration of daidzein, or combined genistein, daidzein, and glycitein (5:4:1) in the ratio found in soy foods, increased mammary tumor growth and metastasis in a mouse model. Dietary daidzein or soy isoflavones upregulated gene expression of eukaryotic protein synthesis initiation factors eIF4E and eIF4G, as well as protein expression of pro-cancer molecules sensitive to elevated eIF4E and eIF4G levels. Subsequently, we published that equol, a metabolite of daidzein produced by intestinal bacteria, is a pivotal soy isoflavone that contributes to cancer malignancy by increasing the expression of proteins that govern metastasis. This proposal will build upon the results of the previous award by testing the hypothesis that soy isoflavones regulate cancer progression via regulation of protein synthesis initiation. Human metastatic breast cancer cell lines that represent various breast cancer types: estrogen receptor positive, triple negative, and HER2 type, will be used for the following Specific Aims. Specific Aim 1 will delineate the effects of individual or combined soy isoflavones, genistein, daidzein, equol, and glycitein, on regulation of protein synthesis initiation and cell functions relevant to cancer progression in vitro. This Aim wll also determine the contribution of soy-isoflavone-mediated upregulation of eIF4G and eIF4E to cancer progression by testing the effects of eIF4G or eIF4E knockdown, or rapamycin to inhibit eIF4E. Since equol increased the expression of the central transcription factor c-Myc, a role for c-Myc in upregulation of protein synthesis initiation factors in response to soy isoflavones will also be tested. Specific Aim 2 will validate the role of the daidzein metabolite equol as the key cancer promoting component of soy isoflavones. The effect of equol on metastasis, individually or in combination with genistein and glycitein, will be determined in immunocompromised mice with mammary tumors established from metastatic human breast cancer cells. Mice will also be treated with control or small interfering RNA (siRNA) to eIF4G to investigate a role for eIF4G in equol-mediated tumor growth and metastasis. Extracted tumors and lung metastases from this Aim will also be tested for expression of pro-cancer molecules. This comprehensive experimental strategy is expected to delineate the molecular basis for potential detrimental effects of soy consumption in breast cancer patients and survivors. Therefore, the proposed research is highly relevant to the mission of the National Institute of General Medical Sciences.

描述（由申请人提供）：该提案的广泛、长期目标是阐明大豆食品对转移性癌症的影响。原发性肿瘤或循环系统中的转移性癌细胞可能通过多种触发因素（包括饮食和环境因素）在远处建立继发性转移。人们已经针对膳食大豆在癌症预防方面开展了大量工作，但在已确诊癌症的转移方面尚未开展研究。因此，该提案弥补了有关主要大豆异黄酮在转移性乳腺癌中的作用和分子靶点的知识空白。理由来自上一次 SC3 颁奖期间生成的数据。我们报道称，在小鼠模型中，按大豆食品中的比例添加大豆黄酮或组合金雀异黄酮、大豆黄酮和黄豆黄素（5:4:1）可增加乳腺肿瘤的生长和转移。膳食黄豆苷元或大豆异黄酮上调真核蛋白质合成起始因子 eIF4E 和 eIF4G 的基因表达，以及对 eIF4E 和 eIF4G 水平升高敏感的前癌分子的蛋白质表达。随后，我们发表了雌马酚（肠道细菌产生的大豆黄酮的代谢物）是一种关键的大豆异黄酮，它通过增加控制转移的蛋白质的表达而导致癌症恶性肿瘤。该提案将建立在先前奖项结果的基础上，通过测试大豆异黄酮通过调节蛋白质合成起始来调节癌症进展的假设。代表各种乳腺癌类型的人类转移性乳腺癌细胞系：雌激素受体阳性、三阴性和 HER2 型，将用于以下具体目标。具体目标 1 将描述单独或组合的大豆异黄酮、染料木黄酮、大豆黄酮、雌马酚和黄豆黄素对调节与体外癌症进展相关的蛋白质合成起始和细胞功能。该目标还将通过测试 eIF4G 或 eIF4E 敲低或雷帕霉素抑制 eIF4E 的效果，确定大豆异黄酮介导的 eIF4G 和 eIF4E 上调对癌症进展的贡献。由于雌马酚增加了中央转录因子 c-Myc 的表达，因此还将测试 c-Myc 在响应大豆异黄酮而上调蛋白质合成起始因子中的作用。具体目标 2 将验证黄豆苷元代谢物牛马酚作为大豆异黄酮的关键促癌成分的作用。雌马酚单独或与金雀异黄素和黄豆黄素联合使用对转移的影响将在具有由转移性人乳腺癌细胞建立的乳腺肿瘤的免疫功能低下的小鼠中测定。小鼠还将接受 eIF4G 的对照或小干扰 RNA (siRNA) 治疗，以研究 eIF4G 在雌马酚介导的肿瘤生长和转移中的作用。从该目标中提取的肿瘤和肺转移瘤也将用于测试促癌分子的表达。这项综合实验策略有望阐明食用大豆对乳腺癌患者和幸存者产生潜在有害影响的分子基础。因此，拟议的研究与国家普通医学科学研究所的使命高度相关。