MECHANISMS OF ANTIESTROGENICITY BY DIOXIN

二恶英的抗雌激素机制

• 批准号: 2767142
• 负责人: WILLIAM G ANGUS
• 金额: $ 3.18万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-03-15 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/2767142
• 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; heregulin; 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)可通过多种途径影响乳腺癌 机制。多环芳香族碳氢化合物由 细胞色素P450，特别是P450-1A1(CYP1A1)对活性物质的作用 会导致乳腺癌。TCDD，通过芳香烃受体 (AHR)可诱导多种基因，包括细胞色素P450-1A1和细胞色素P450-1B1。AHR 相对于CYP1A1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- 诱导细胞色素P1B1表达，提示内质网可能不是普遍存在的 AhR活动所必需的。TCDD也显示出抗雌激素活性 乳房细胞。AHR活性对内质网的依赖性将通过 比较TCDD诱导基因(CYP1A1， ER-(MDA-MB-231)和ER+(MCF7)细胞株和正常人 用或不用ER拮抗剂ICI 182780处理乳腺上皮细胞。丙二醛- MB-231细胞分泌ErbB2/3刺激物HERG。在ER+细胞中， HRG可降低ER，从而抑制AhR介导的基因诱导。这 假说将通过检测TCDD-的表达和活性来检验。 在存在/不存在HRG的情况下，诱导ER敏感基因(例如，CYP1A1)。 HRG诱导细胞色素P1A1作用的时程可能与 假定内质网丢失。TCDD的抗雌激素作用可能是 通过erbB2/3。这种可能性将通过比较 TCDD存在或不存在时erbB2/3的表达和活性

项目成果

TCDD elevates erbB2 expression and signaling in T47D cells by reversing serum potentiation of estrogen receptor activity, independent of estrogen levels and enhanced ER down-regulation.

TCDD 通过逆转雌激素受体活性的血清增强作用来提高 T47D 细胞中 erbB2 的表达和信号传导，与雌激素水平无关并增强 ER 下调。

• DOI: 10.1016/s0303-7207(00)00337-3
• 发表时间: 2000
• 期刊: Molecular and cellular endocrinology
• 影响因子: 4.1
• 作者: Angus,WG;CampaigneLarsen,M;Jefcoate,CR
• 通讯作者: Jefcoate,CR