MECHANISMS OF ANTIESTROGENICITY BY DIOXIN

二恶英的抗雌激素机制

• 批准号: 2391591
• 负责人: WILLIAM G ANGUS
• 金额: $ 2.99万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-03-15 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/2391591
• 关键词: MCF7 cell; breast neoplasms; chemical carcinogen; chemical related neoplasm /cancer; cytochrome P450; dioxins; environmental toxicology; estrogen inhibitor; estrogen receptors; gene expression; gene induction /repression; human tissue; toxicant interaction

Tetrachlorodibenzo-p-dioxin (TCDD) may affect breast cancer by multiple mechanisms. Polycyclic aromatic hydrocarbons are metabolized by the cytochromes P450, notably P450-1A1 (CYP1A1), to reactive species contributing to breast cancer. TCDD, via the aryl hydrocarbon receptor (AhR) induces numerous genes, including CYP1A1 and P450-1B1 (CYP1B1). AhR activity, with respect to CYP1A1, depends on the estrogen receptor (ER). Preliminary data indicate that the ER is not required for basal or TCDD- induced expression of CYP1B1, suggesting that ER may not be universally required for AhR activity. TCDD also exhibits antiestrogenic activity in breast cells. The dependence of AhR activity on ER will be examined by comparing the expression and activity of TCDD-inducible genes (CYP1A1, CYP1B1) in ER- (MDA-MB-231) and ER+ (MCF7) cell lines and normal human mammary epithelia treated with/without the ER antagonist ICI 182780. MDA- MB-231 cell secrete the erbB2/3 stimulant heregulin (HRG). In ER+ cells, HRG may decrease ER, thus suppressing AhR-mediated gene induction. This hypothesis will be tested by examining expression and activity of TCDD- induced, ER-sensitive genes (e.g. CYP1A1) in the presence/absence of HRG. A timecourse of HRG's effect of CYP1A1 induction will be related to postulated loss of ER. The antiestrogenic effects of TCDD could be mediated via erbB2/3. This possibility will be examined by comparing the expression and activity of erbB2/3 in the presence/absence of TCDD.

四氯二苯并对二恶英（TCDD）可能通过多种途径影响乳腺癌 机制等多环芳烃是由 细胞色素P450，特别是P450- 1A 1（CYP 1A 1），对反应性物质 会导致乳腺癌TCDD，通过芳香烃受体 (AhR)诱导许多基因，包括CYP 1A 1和P450- 1B 1（CYP 1B 1）。AHR CYP 1A 1的活性取决于雌激素受体（ER）。 初步数据表明，基础或TCDD不需要ER- 诱导CYP 1B 1的表达，这表明ER可能不是普遍的 是AhR活动所必需的。TCDD还表现出抗雌激素活性， 乳腺细胞将通过以下方法检查AhR活性对ER的依赖性 比较TCDD诱导基因（CYP 1A 1， ER-（MDA-MB-231）和ER+（MCF 7）细胞系和正常人中的CYP 1B 1） 用/不用ER拮抗剂ICI 182780处理的乳腺上皮。MDA- MB-231细胞分泌erbB 2/3刺激剂heregulin（HRG）。在ER+细胞中， HRG可降低ER，从而抑制AhR介导的基因诱导。这 将通过检测TCDD的表达和活性来检验假设- 在存在/不存在HRG的情况下诱导ER敏感基因（例如CYP 1A 1）。 HRG对CYP 1A 1诱导作用的时间进程与以下因素有关： 假设ER丢失。TCDD的抗雌激素作用可能是 通过erbB 2/3介导。这种可能性将通过比较 erbB 2/3在TCDD存在/不存在下的表达和活性。