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

描述(申请人提供)：这项研究的长期目标是更好地了解饮食中的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，已被证明是一种非常有效的癌症阻滞剂，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，如吸烟致癌物质，可能与儿童和年轻人的癌症有关。最近一项使用经胎盘的小鼠癌症模型的研究表明，母亲摄入I3C与致癌物暴露一致，显著降低了10个月大的婴儿因侵袭性胸腺淋巴瘤和肺癌多发性而导致的子代死亡率。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基因敲除小鼠模型来评估I3C在子宫内暴露于环境致癌物质二苯并[a，L]芘(DBP)的后代中预防癌症的治疗效果。ERβ是胸腺和肺中表达的主要ER亚型。工作假设是，I3C对DBP诱导的经胎盘癌变的保护作用需要ERbeta的表达。用来验证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的肿瘤起始和肿瘤促进阶段作为化学预防剂的有效性。在后代中评估的终点包括淋巴瘤依赖死亡率、肺和肝脏肿瘤结果、形态测量数据和肿瘤的全球基因表达谱。胎儿是环境化合物的敏感目标，一生中接触化学致癌物的很大一部分发生在怀孕和整个母乳喂养过程中。有证据表明，孕妇在怀孕期间食用某些蔬菜或从植物中提取的化合物，如吲哚-3-甲醇，可以预防儿童和成年后代患癌症。然而，目前对吲哚-3-甲醇对胎儿产生癌症阻断作用的机制缺乏了解，这引发了人们对其作为人类癌症预防和/或治疗剂的可能效用的质疑。

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.