Molecular targets of soy isoflavones in breast cancer progression

描述（由申请人提供）：本提案的广泛、长期目标是阐明大豆食品对转移性癌症的影响。原发肿瘤中的转移性癌细胞或循环中的转移性癌细胞可通过多种触发因素（包括饮食和环境因素）在远处建立继发性转移。膳食大豆在预防癌症方面已经做了很多工作，但在癌症转移方面还没有。因此，这一建议解决了关于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。其基本原理来自于之前SC3授予过程中产生的数据。我们报道了在小鼠模型中，膳食中添加大豆黄素，或大豆黄素、大豆黄素和糖苷的组合（5:4:1），在大豆食品中发现的比例增加了乳腺肿瘤的生长和转移。膳食中的大豆黄素或大豆异黄酮上调真核蛋白合成起始因子eIF4E和eIF4G的基因表达，以及对eIF4E和eIF4G水平升高敏感的促癌分子蛋白表达。随后，我们发表了马酚，一种由肠道细菌产生的大豆苷元代谢物，是一种关键的大豆异黄酮，通过增加控制转移的蛋白质表达来促进癌症恶性。这项提案将建立在先前奖项的结果之上，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。人类转移性乳腺癌细胞系代表各种乳腺癌类型：雌激素受体阳性，三阴性和HER2型，将用于以下特定目的。特异性目标1将描述单独或组合大豆异黄酮，染料木素，大豆苷元，雌马酚和糖苷对调节的影响

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.