Genistien and prevention of HER2-overexpressing breast *

描述（由申请人提供）： 本申请的重点是大豆植物化学物质对预防雌激素受体阳性[ER（+）]和HER 2过度表达乳腺癌（BRCA）进展的影响。假设大豆异黄酮对ER（+）/HER 2过表达的人乳腺癌具有有效的抗进展作用，部分是通过调节HER 2和ER-α信号通路。支持这一假设的基本原理是基于以前的研究和我们的初步研究结果，总结如下：（1）。近40%的ER（+）乳腺肿瘤对抗雌激素治疗（如他莫昔芬（TAM））无反应。(2)HER 2基因的过表达已被证明在从乳腺癌敏感表型发展为乳腺癌不敏感表型的过程中发挥关键作用。(3)我们的初步研究表明，大豆异黄酮显着抑制ER（+）/HER 2过表达BT-474人BRCA细胞在体外的生长，部分通过下调ER α和HER 2。染料木黄酮可能是一种有效的药物，用于预防和治疗HER 2过表达的人类乳腺肿瘤。本试验旨在探索染料木黄酮和富含染料木黄酮的大豆植物化学物质在预防HER 2过表达BRCA中的可能作用，并阐明染料木黄酮抑制HER 2过表达乳腺肿瘤的可能机制。具体目标1是确定染料木黄酮和富含染料木黄酮的大豆植物化学物质对临床相关乳腺肿瘤模型中BT-474细胞的生长抑制作用。将HER 2过表达BT-474乳腺癌细胞植入补充雌激素的小鼠的乳腺脂肪垫中，以产生ER（+）/HER 2过表达乳腺肿瘤。将评价染料木黄酮、大豆植物化学物质混合物（大豆植物化学物质浓缩物）和TAM单独以及染料木黄酮和TAM组合对BT-474肿瘤的生长抑制活性。具体目标2是确定染料木黄酮有效抑制HER 2过表达BRCA生长的分子机制。将确定一系列肿瘤生物标志物，以阐明可能的作用机制。我们将确定与雌激素途径相关的生物标志物，如ER α和ER β的肿瘤表达。然后，我们将定量HER 2和EGFR以及MAPK和PI 3 K/Akt的肿瘤水平。同时测定肿瘤增殖指数、凋亡指数、肿瘤微血管密度。这些体内生物测定和机理研究将有望为将来考虑单独和/或与TAM组合应用染料木黄酮和/或富含染料木黄酮的大豆植物化学组分预防和治疗ER（+）/HER 2-过表达乳腺癌提供重要见解。

DESCRIPTION (provided by applicant): This application is focused on the effects soy phytochemicals on preventing the progression of estrogen receptor-positive [ER(+)]and HER2-overexpressing breast cancer (BRCA). The hypothesis is that soy isoflavone genistein has a potent anti-progression effect on ER(+)/HER2-overexpressing human breast cancer in part by modulating HER2 and ER-alpha signaling pathways. The rationale for supporting this hypothesis is based on previous research and our preliminary findings, as summarized in the followings: (1). Nearly 40% of ER(+) breast tumors do not respond to antiestrogen treatment such as tamoxifen (TAM). (2) Overexpression of the HER2 gene has been shown to play a critical role in the development of hormone-insensitive BRCA from the hormone-sensitive phenotype. (3) Our preliminary studies indicate that soy isoflavone genistein significantly inhibited the growth of ER(+)/HER2-overexpressing BT-474 human BRCA cells in vitro in part via down-regulation of ERalpha and HER2. It is possible that genistein may be an effective agent for the prevention and treatment of HER2-overexpressing human breast tumors. This pilot application is to explore the possible role of genistein and genistein-rich soy phytochemicals in prevention of HER2-overexpresisng BRCA and to elucidate the possible underlying mechanisms by which genistein inhibits HER2-overexpressing breast tumors. Specific aim 1 is to determine the growth-inhibition effect of genistein and genistein-rich soy phytochemicals on BT-474 cells in a clinically relevant breast tumor model. HER2-overexpressing BT-474 breast cancer cells will be implanted into the mammary fat pad of the mice supplemented with estrogens to develop ER(+)/HER2-overexpressing breast tumor. Genistein, soy phytochemicals mixture (soy phytochemical concentrate) and TAM, alone and genistein and TAM combinations, will be evaluated for their growth inhibition activities to BT-474 tumors. Specific aim 2 is to determine the molecular mechanisms by which genistein effectively inhibits the growth of HER2-overexpressing BRCA. A series of tumor biomarkers will be determined to elucidate the possible mechanisms of action. We will determine the biomarkers that are related to estrogen-pathways such as tumor expressions of ERalpha and ERbeta. We will then quantify tumor levels of HER2 and EGFR, and MAPK and PI3K/Akt. Tumor proliferation index, apoptotic index tumor microvessel density will also be determined. These in vivo bioassays and mechanistic studies will be expected to provide significant insight into the future consideration of applying genistein and/or genistein-rich soy phytochemical fractions, alone and/or in combination with TAM, for prevention and treatment of ER(+)/HER2- overexpressing breast cancer.