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

基本信息

批准号：
7320293
负责人：
Abby D Benninghoff
金额：
$ 2.44万
依托单位：
OREGON STATE UNIVERSITY
依托单位国家：
美国
项目类别：
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/7320293
关键词：
Address Adult Andro-Diane Animal Cancer Model Animal Model Animals Apoptosis Aryl Hydrocarbon Receptor Breast Breast Feeding Broccoli - dietary Cabbage - dietary Cancer Model Carcinogen Metabolism Carcinogen exposure Carcinogens Cell Cycle Progression Chemicals Chemoprevention Chemopreventive Agent Chemoprotective Agent Child Childhood Colon Consumption DNA Repair Data Dibenzo (a,l) pyrene Diet Dietary Factors Dietary Indole Dietary Phytochemical Disease End Point Environment Environmental Carcinogens Estrogen Receptor beta Estrogen Receptors Estrogens Exposure to Fetus Gene Expression Genus Cola Goals Health Hepatocarcinogenesis Human Incidence Indole-3-Carbinol Infant Kidney Knock-out Knowledge Laboratories Link Liver Liver neoplasms Lung Lung Adenoma Lung Neoplasms Lymphoma Malignant Neoplasms Malignant neoplasm of lung Mediating Methanol Molecular Profiling Mus Nuclear Outcome Perinatal Carcinogenesis Perinatal Exposure Phase Phytochemical Phytoestrogens Plants Pregnancy Prevention Preventive Process Property Protocols documentation Pyrenes Rattus Reducing Agents Research Risk Role Salmo trutta Skin Cancer Smoke Spleen Testing Therapeutic Therapeutic Agents Thymic Lymphoma Thymus Gland Transplacental Carcinogenesis Treatment Efficacy Tumor Promotion Tumor Tissue Vegetables Work cancer chemoprevention cancer prevention cancer risk carcinogenesis chemical carcinogen cruciferous vegetable design dietary supplements environmental chemical expectation in utero innovation middle age mortality mouse model prevent protective effect pyrene receptor size transcription factor tumor tumor initiation tumorigenesis young adult

项目摘要

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 (ISC), 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 ISC 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 ISC 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 ISC was not dependent on the AhR. Thus, while ISC 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 ISC in prevention of cancer in offspring exposed in utero to the environmental carcinogen dibenzo[a,l]pyrene (DBP) will be evaluated using an ERP knockout mouse model. ER(3 is the major ER subtype expressed in the thymus and lung. The working hypothesis is that protection by ISCagainst DBP-induced transplacental carcinogenesis requires ERP 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 ISCas a chemopreventive agent during tumor initiation and tumor promotion phases in both ERP 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.

这项研究的长期目标是更好地了解饮食如何植物化学物质可以影响人类健康和疾病，吲哚-3-甲醇（ISC）是一种关键的活性成分十字花科蔬菜中的一种，已被证明是一种非常有效的癌症阻断剂，可以减少患肺癌、结肠癌、乳腺癌和皮肤癌的风险。人们非常担心胎儿暴露于环境中怀孕期间的化学物质，例如烟雾致癌物，可能与儿童和青少年有关癌症。最近一项使用经胎盘小鼠癌症模型的研究表明，母亲食用 ISC 与致癌物暴露同时发生，由于侵袭性胸腺而显着降低了后代死亡率 10 个月大的后代中淋巴瘤和肺部肿瘤的多样性。化学预防特性 ISC 可能涉及多种作用机制，包括与芳烃受体的相互作用 (AhR) 和雌激素受体 (ER)。在这项先前的经胎盘癌症研究中，化学预防 ISC 的财产不依赖于 AhR。因此，虽然 ISC 是一种有效的化学保护化合物经胎盘发挥保护作用的机制尚不清楚。为了解决这个关键问题知识差距，ISC 在预防子宫内暴露于 ISC 的后代癌症方面的治疗效果环境致癌物二苯并[a,l]芘 (DBP) 将使用 ERP 敲除小鼠模型进行评估。 ER(3 是在胸腺和肺中表达的主要 ER 亚型。工作假设是保护作用通过ISC对抗DBP诱导的经胎盘癌发生需要ERP表达。实验的检验这一假设的方法包括一项为期 10 个月的经胎盘癌症研究，利用特定的饮食方案来测试 ISCas（一种化学预防剂）在肿瘤发生过程中的功效，以及 ERP 阳性和阴性妊娠环境中的肿瘤促进阶段。端点为对后代的评估包括淋巴瘤依赖性死亡率、肺和肝肿瘤结果、形态测量肿瘤的数据和全局基因表达谱。胎儿是环境化合物的敏感目标，并且是一生的重要组成部分在怀孕期间和整个母乳喂养过程中都会接触化学致癌物。证据表明母亲食用某些蔬菜或植物源性化合物，例如吲哚-3- 怀孕期间的甲醇可以预防后代儿童和成人癌症。然而，目前缺乏了解吲哚-3-甲醇对胎儿发挥其癌症阻断作用的机制提出了关于其作为人类癌症的预防和/或治疗剂的可能用途的问题。