Effects of herbs on transcription and cell proliferation

草药对转录和细胞增殖的影响

• 批准号: 6655134
• 负责人: DALE C LEITMAN
• 金额: $ 22.71万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-15 至 2004-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6655134
• 关键词: Adenoviridae; DNA replication; MCF7 cell; alternative medicine; breast neoplasms; carcinogenesis; cell proliferation; estrogen receptors; flavones; gene expression; gene induction /repression; genetic transcription; medicinal plants; phytoestrogens; plant extracts; polymerase chain reaction; protein isoforms; tissue /cell culture; transcription factor; tumor necrosis factor alpha

DESCRIPTION (provided by applicant): Multiple lines of evidence indicate that estrogens promote breast cancer, Selective estrogen receptor modulators (SERMs), such as tamoxifen are first-line drugs used as adjuvant therapy for preventing recurrences and reducing mortality in women with a history of breast cancer. More recently, SERMs are becoming increasingly popular for preventing cancer, since studies found that tamoxifen and raloxifene reduce the incidence of estrogen receptor positive breast tumors. Although the exact mechanism whereby SERMs prevent breast cancer is unknown, it is clear that SERMs interact directly with two known estrogen receptors, ER-alpha and ER-beta. Understanding the role of ER-alpha or ER-beta is critical for identifying more selective SERMs for the prevention and treatment of breast cancer. Our studies with MCF-7 cells indicate that ER-alpha mediates cell proliferation in response to estrogens. The role of ER-beta is breast cancer is unknown. Yet, our studies indicate that a large percentage of ER positive and ER negative tumors contain ER-beta. Furthermore, our results indicate that ER-beta inhibits the growth of breast tumors. The increased DNA synthesis caused by estradiol is inhibited by 50% in MCF-7 cells infected with an adenovirus that expresses ER-beta. High intake of plant estrogens (phytoestrogens) is associated with a low incidence of breast cancer, A key question is: Why do estrogens increase the risk of breast cancer, whereas phytoestrogens might decrease the risk of breast cancer? Our studies with isoflavones suggest that the divergent action of estrogens and phytoestrogens on breast cells may result from differences in their ability to trigger transcriptional functions of ER-alpha or ER-beta. Based on these studies, we have hypothesized that estrogens increase breast cancer by interacting with ER-alpha to stimulate cell proliferation, whereas phytoestrogens may prevent breast cancer by interacting with ER-beta. It is known that tamoxifen and raloxifene interact with both ERs non-selectively. We have hypothesized that herbs used in Traditional Chinese Medicine to prevent and treat breast cancer may contain natural SERMs that selectively interact with ER-alpha or ER-beta Our preliminary data with 71 herbs indicates that like, isoflavones, some Chinese herbs also possess estrogenic activity and interact selectively with ER-alpha or ER-beta The major goal of this application is identify Chinese herbs that selectively trigger ER-beta or block ER-alpha transcriptional pathways, because we hypothesize that these herbs will be less likely to elicit proliferative effects on breast cells, compared to estrogens. To accomplish this goal, we will determine the effects of the individual herbs on: (1) proliferation of breast cancer cells (2) transcriptional repression and activation by ER-alpha or ER-beta (2) binding to purified ER-alpha or ER-beta (3) recruitment of co-regulator proteins to ER-alpha or ER-beta and (4) expression of growth promoting genes. These studies have the potential to determine the molecular mechanism whereby herbs differentially interact with ER-alpha or ER-beta to regulate gene transcription and cell proliferation. This information can also provide a scientific basis to prioritize herbs for clinical trials evaluation for their ability to prevent and treat breast cancer.

描述（由申请人提供）：多条证据表明雌激素促进乳腺癌，选择性雌激素受体调节剂（SERM），如他莫昔芬是一线药物，用作预防复发和降低有乳腺癌病史的女性死亡率的辅助治疗。最近，SERM在预防癌症方面越来越受欢迎，因为研究发现他莫昔芬和雷洛昔芬可降低雌激素受体阳性乳腺肿瘤的发病率。虽然SERM预防乳腺癌的确切机制尚不清楚，但很明显，SERM直接与两种已知的雌激素受体ER-α和ER-β相互作用。了解ER-α或ER-β的作用对于确定用于预防和治疗乳腺癌的更具选择性的SERM至关重要。我们对MCF-7细胞的研究表明，ER-α介导细胞增殖对雌激素的反应。ER-β在乳腺癌中的作用尚不清楚。然而，我们的研究表明，大部分ER阳性和ER阴性肿瘤含有ER-β。 此外，我们的研究结果表明ER-β抑制乳腺肿瘤的生长。在用表达ER-β的腺病毒感染的MCF-7细胞中，雌二醇引起的DNA合成增加被抑制50%。 高摄入植物雌激素（植物雌激素）与乳腺癌的低发病率有关，一个关键问题是：为什么雌激素会增加乳腺癌的风险，而植物雌激素可能会降低乳腺癌的风险？我们对雌激素的研究表明，雌激素和植物雌激素对乳腺细胞的不同作用可能是由于它们触发ER-α或ER-β转录功能的能力不同。基于这些研究，我们假设雌激素通过与ER-α相互作用刺激细胞增殖来增加乳腺癌，而植物雌激素可能通过与ER-β相互作用来预防乳腺癌。已知他莫昔芬和雷洛昔芬非选择性地与两种ER相互作用。我们假设在传统中医中用于预防和治疗乳腺癌的草药可能含有选择性地与ER-α或ER-β相互作用的天然SERMs。我们对71种草药的初步数据表明，一些中草药也具有雌激素活性，并选择性地与ER-α或ER-β相互作用。本申请的主要目的是鉴定选择性地触发ER-β的中草药。β或阻断ER-α转录途径，因为我们假设这些草药与雌激素相比，不太可能引起乳腺细胞的增殖作用。为了实现这一目标，我们将确定单个草药对以下方面的影响：（1）乳腺癌细胞的增殖（2）ER-α或ER-β的转录抑制和激活（2）与纯化的ER-α或ER-β的结合（3）辅助调节蛋白向ER-α或ER-β的募集和（4）生长促进基因的表达。这些研究有可能确定草药与ER-α或ER-β差异相互作用以调节基因转录和细胞增殖的分子机制。这些信息还可以提供科学依据，以优先考虑临床试验评估其预防和治疗乳腺癌的能力。