Role of estrogen receptor beta in cancer prevention by dietary indole-3-carbinol

雌激素受体β在膳食吲哚-3-甲醇预防癌症中的作用

• 批准号: 7221809
• 负责人: Abby D Benninghoff
• 金额: $ 4.68万
• 依托单位: OREGON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-11-15 至 2008-11-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7221809
• 关键词: benzopyrenes; cancer prevention; carcinogens; chemoprevention; disease /disorder model; embryo /fetus toxicology; environment related neoplasm /cancer; environmental exposure; estrogen receptors; genetically modified animals; indoles; laboratory mouse; neoplasm /cancer nutrition therapy; nonhuman therapy evaluation; nutrition aspect of cancer; nutrition related tag; phytoestrogens; postdoctoral investigator

DESCRIPTION (provided by applicant): The long-term goal of this research is to develop a better understanding of how dietary phytochemicals can influence human health and disease, lndole-3-carbinol (I3C), a key active component of cruciferous vegetables, has been shown to be a remarkably effective cancer blocking agent by reducing risk of lung, colon, breast and skin cancer. There is great concern that fetal exposure to environmental chemicals during pregnancy, such as smoke carcinogens, could be linked to childhood and young adult cancers. A recent study using a transplacental mouse cancer model showed that maternal consumption of I3C coincident with carcinogen exposure markedly decreased offspring mortality due to aggressive thymic lymphoma as well as lung tumor multiplicity in 10 month-old offspring. The chemopreventive properties of I3C can involve multiple mechanisms of action, including interaction with the aryl hydrocarbon receptor (AhR) and the estrogen receptor (ER). In this prior transplacental cancer study, the chemopreventive property of I3C was not dependent on the AhR. Thus, while I3C is an effective chemoprotective compound transplacentally, the mechanism by which it exerts its protective effects is unknown. To address this critical knowledge gap, the therapeutic efficacy of I3C in prevention of cancer in offspring exposed in utero to the environmental carcinogen dibenzo[a,l]pyrene (DBP) will be evaluated using an ERbeta knockout mouse model. ERbeta is the major ER subtype expressed in the thymus and lung. The working hypothesis is that protection by I3C against DBP-induced transplacental carcinogenesis requires ERbeta expression. The experimental approach employed to test this hypothesis consists of a 10 month transplacental cancer study utilizing specific dietary protocols to test the efficacy of I3C as a chemopreventive agent during tumor initiation and tumor promotion phases in both ERbeta positive and negative gestating environments. Endpoints to be evaluated in offspring include lymphoma-dependent mortality, lung and liver tumor outcome, morphometric data and global gene expression profiles of tumors. The fetus is a sensitive target for environmental compounds, and a significant portion of lifetime exposure to chemical carcinogens occurs during gestation and throughout breast feeding. Evidence suggests that maternal consumption of certain vegetables or plant-derived compounds, such as indole-3- carbinol, during pregnancy can prevent childhood and adult cancers in offspring. However, the current lack of understanding of the mechanisms by which indole-3-carbinol exerts its cancer blocking effects to the fetus raises questions about its possible utility as a preventive and/or therapeutic agent for human cancer.

描述（由申请人提供）：本研究的长期目标是更好地了解膳食植物化学物质如何影响人类健康和疾病，吲哚-3-甲醇（I3C）是十字花科蔬菜的关键活性成分，具有已被证明是一种非常有效的癌症阻断剂，可降低肺癌、结肠癌、乳腺癌和皮肤癌的风险。人们非常担心，胎儿在怀孕期间接触环境化学物质（例如烟雾致癌物质）可能与儿童和青少年癌症有关。最近一项使用经胎盘小鼠癌症模型的研究表明，母亲摄入 I3C 的同时暴露于致癌物，可显着降低 10 个月大的后代因侵袭性胸腺淋巴瘤和肺肿瘤多样性引起的后代死亡率。 I3C 的化学预防特性可能涉及多种作用机制，包括与芳烃受体 (AhR) 和雌激素受体 (ER) 的相互作用。在这项先前的经胎盘癌症研究中，I3C 的化学预防特性不依赖于 AhR。因此，虽然 I3C 是一种有效的经胎盘化学保护化合物，但其发挥保护作用的机制尚不清楚。为了解决这一关键的知识差距，将使用 ERbeta 敲除小鼠模型评估 I3C 在子宫内暴露于环境致癌物二苯并[a,l]芘 (DBP) 的后代中预防癌症的治疗效果。 ERbeta 是在胸腺和肺中表达的主要 ER 亚型。目前的假设是，I3C 对 DBP 诱导的经胎盘癌发生的保护作用需要 ERbeta 表达。用于检验这一假设的实验方法包括一项为期 10 个月的经胎盘癌症研究，利用特定的饮食方案来测试 I3C 在 ERbeta 阳性和阴性妊娠环境中肿瘤起始和肿瘤促进阶段作为化学预防剂的功效。在后代中评估的终点包括淋巴瘤依赖性死亡率、肺和肝肿瘤结果、形态测量数据和肿瘤的整体基因表达谱。胎儿是环境化合物的敏感目标，一生中很大一部分接触化学致癌物的情况发生在妊娠期间和整个母乳喂养期间。有证据表明，母亲在怀孕期间食用某些蔬菜或植物源性化合物（例如吲哚-3-甲醇）可以预防后代的儿童和成人癌症。然而，目前对吲哚-3-甲醇对胎儿发挥其癌症阻断作用的机制缺乏了解，引发了对其作为人类癌症预防和/或治疗剂的可能用途的疑问。