ENVIRONMENTAL ESTROGENS AND BREAST CANCER

描述(申请人的描述)我们的产品中使用的许多化合物 工业社会，包括杀虫剂、塑化剂、二恶英和 其他外源物质，可归类为“环境雌激素”。 最近的临床流行病学研究对以下问题存在分歧： 环境雌激素导致了观察到的乳房增长 癌症发病率。理解两国关系的关键 环境雌激素对乳腺癌的作用机制 无论它们是直接通过雌激素受体起作用，还是它们 产生雌激素样效应并改变乳腺细胞生物学 机械装置。关键是要知道化合物是否能结合到 雌激素受体不佳仍具有雌激素样作用。此外，还有 需要一种更有效的方法来筛选化合物中的雌激素和 对人体乳房的抗雌激素作用。这一试点项目 通过关注模型非类固醇雌激素来解决这些问题， 多西辛醇/烯丙醇化合物。就像众多潜在的 它们所代表的环境雌激素，这些化合物证明 强大的生物学效应，但与雌激素受体的结合较差。也是 它们有着截然不同的历史，在人类和 动物物种。因此，它们处于解决这些问题的理想位置 关于环境雌激素和环境雌激素的重要和当前问题 乳腺癌病因学。申请者的目标是检验假设 尽管对雌激素的亲和力很低，但多西辛酸/烯醇酸 受体，通过经典雌激素介导其雌激素样作用 受体。我们将对每一种分子功能进行分析 雌激素受体。此外，申请人将决定 受体依赖于每种基因调控机制。这个 申请者将评估雌激素受体介导的雌激素和雌激素 用人乳腺细胞系比较受体非依赖性机制 化合物对17β-雌二醇的激活和抑制作用 内源基因。最后，申请者将专门测试 这些化合物表现出的表面悖论的解释，高 受体亲和力低的生物活性。通过探索这些 化合物和它们所呈现的明显的悖论，增加了对 非类固醇环境雌激素的作用机制 被获得了。这个试点项目将验证这些分子方法。 为了定义雌激素活性，首先是我们的模型化合物，在 未来，用于评估其他化学品。所有这些目标都有 乳腺癌的病因及其作用的直接关系 化学物质和荷尔蒙。

DESCRIPTION (Applicant's Description) Many compounds used in our industrial society, including insecticides, plasticizers, dioxins, and other xenobiotics, can be classified as "environmental estrogens." Recent clinical epidemiological studies are split as to whether environmental estrogens contribute to the observed increases in breast cancer incidence. Key to understanding the relationship of environmental estrogens to breast cancer is their mechanism of action whether they act directly through the estrogen receptor or whether they produce estrogen-like effects and alter breast cell biology by other mechanisms. It is critical to know whether compounds that bind to estrogen receptor poorly still have estrogenic effects. Also, there is a need for a more effective way to screen compounds for estrogenic and anti-estrogenic effects on the human breast. This pilot project addresses these issues by focusing on model non-steroidal estrogens, the Doisynolic/Allenolic compounds. Like the multitude of potential environmental estrogens they represent, these compounds demonstrate potent biological effects, yet bind to estrogen receptor poorly. Also they have a distinct history of differing potencies in humans versus animal species. Thus, they are ideally positioned to address these important and current issues regarding environmental estrogens and breast cancer etiology. The applicant's goal is to test the hypothesis that Doisynolic/Allenolic acids, in spite of low affinity for estrogen receptor, mediate their estrogenic effects through the classic estrogen receptor. We will use assays for each of the molecular functions of estrogen receptor. In addition, the applicant will determine the receptor dependence for each mechanism of gene regulation. The applicant will evaluate both estrogen receptor mediated and estrogen receptor independent mechanisms using human breast cell lines to compare compounds to 17 beta-estradiol on both the activation and repression of endogenous genes. Finally, the applicant will specifically test explanations of the apparent paradox these compounds exhibit, high biological activity with low receptor affinity. By exploring these compounds and the apparent paradox they present, increased understanding of the mechanisms of action of non-steroidal environmental estrogens will be gained. This pilot project will validate these molecular approaches for defining estrogenic activity, first for our model compounds and, in the future, for evaluation of other chemicals. All of these goals have a direct relationship to the etiology of breast cancer and the actions of chemicals and hormones.