Genistien and prevention of HER2-overexpressing breast *

Genistien 和预防 HER2 过度表达的乳房 *

• 批准号: 6951520
• 负责人: JIN-RONG ZHOU
• 金额: $ 8.5万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-21 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6951520
• 关键词: antineoplastics; biological signal transduction; biomarker; cell line; cell proliferation; chemoprevention; estrogen analog; gene expression; genistein; laboratory mouse; mitogen activated protein kinase; neoplastic cell; pathologic process; phosphatidylinositol 3 kinase; protooncogene; soybeans

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.

描述（由申请人提供）： 该应用集中于大豆植物化学物质对防止雌激素受体阳性[ER（+）]和过表达HER2过表达的乳腺癌（BRCA）进展的影响。假设是，大豆异黄酮染料黄酮对ER（+）/HER2过表达的人类乳腺癌具有有效的抗突出作用，部分原因是调节HER2和ER-Alpha信号传导途径。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发现，如以下内容所述：（1）。近40％的ER（+）乳腺肿瘤对抗雌激素治疗（例如他莫昔芬（TAM））没有反应。 （2）HER2基因的过表达已被证明在激素对激素敏感表型的激素不敏感BRCA的发展中起关键作用。 （3）我们的初步研究表明，大豆异黄酮染料木黄酮明显抑制了ER（+）/HER2过表达的BT-474人类BRCA细胞的生长，部分原因是通过下调Eralpha和Her2。染料木黄酮可能是预防和治疗HER2过表达的人类乳腺肿瘤的有效药物。该试点应用是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HER2-跨性别的BRCA中的可能作用，并阐明染料蛋白酶抑制HER2过表达的乳腺癌的可能的基本机制。具体目的1是确定在临床相关的乳腺肿瘤模型中，染料木黄酮和富含染料木黄酮的大豆植物化学物质对BT-474细胞的生长抑制作用。过表达HER2的BT-474乳腺癌细胞将植入添加了雌激素的小鼠的乳腺脂肪垫中，以形成ER（+）/HER2过表达的乳腺肿瘤。染料木黄酮，大豆植物化学物质混合物（大豆植物化学浓缩液）和TAM，单独的tam以及染料木黄酮和TAM组合，以评估其对BT-474肿瘤的生长抑制活性。具体目的2是确定染料木黄酮有效抑制HER2过表达BRCA的生长的分子机制。将确定一系列肿瘤生物标志物以阐明可能的作用机理。我们将确定与雌激素轨道相关的生物标志物，例如Eralpha和Erbeta的肿瘤表达。然后，我们将量化HER2和EGFR的肿瘤水平，以及MAPK和PI3K/AKT。还将确定肿瘤增殖指数，凋亡指数肿瘤微血管密度。这些体内生物测定和机械研究将有望提供对未来的考虑以及单独和/或与TAM结合使用染料木黄酮和/或含染料碱性的大豆植物化学分数和/或与TAM结合使用，以预防和治疗ER（+）/HER2-过度表达乳腺癌的良好的考虑。