Safe S, Wormke M, Samudio I
Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station 77843-4466, USA.
J Mammary Gland Biol Neoplasia. 2000 Jul;5(3):295-306. doi: 10.1023/a:1009550912337.
The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that forms a functional heterodimeric complex with the AhR nuclear translocator (Arnt) protein. The environmental toxin, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), is a high affinity ligand for the AhR and has been extensively used to investigate AhR-mediated biochemical and toxic responses. TCDD modulates several endocrine pathways including inhibition of 17beta-estradiol-induced responses in the immature and ovariectomized rodent uterus and mammary gland and in human breast cancer cell lines. TCDD inhibits formation and growth of mammary tumors in carcinogen-induced rodent models and relatively nontoxic selective AhR modulators (SAhRMs) are being developed for treatment of breast cancer. The mechanisms of inhibitory AhR-estrogen receptor (ER) crosstalk have been investigated in MCF-7 breast cancer cells by analysis of promoter regions of genes induced by E2 and inhibited by TCDD. AhR-mediated inhibition of E2-induced cathepsin D, pS2, c-fos, and heat shock protein 27 gene expression involves direct interaction of the AhR complex with inhibitory pentanucleotide (GCGTG) dioxin responsive elements (iDREs) resulting in disruption of interactions between proteins binding DNA elements required for ER action and the basal transcription machinery. Mechanisms of inhibitory AhR-ER crosstalk indicate that functional iDREs are required for inhibition of some genes; however, results indicate that other interaction pathways are important including AhR-mediated proteasome-dependent degradation of the ER.
芳基烃受体（AhR）是一种配体激活的转录因子，它与AhR核转运蛋白（Arnt）形成功能性异源二聚体复合物。环境毒素2,3,7,8-四氯二苯并对二恶英（TCDD）是AhR的高亲和力配体，已被广泛用于研究AhR介导的生化和毒性反应。TCDD调节多种内分泌途径，包括抑制未成熟和去卵巢啮齿动物子宫及乳腺以及人乳腺癌细胞系中17β-雌二醇诱导的反应。TCDD抑制致癌物诱导的啮齿动物模型中乳腺肿瘤的形成和生长，目前正在开发相对无毒的选择性AhR调节剂（SAhRMs）用于治疗乳腺癌。通过分析由E2诱导并被TCDD抑制的基因的启动子区域，在MCF-7乳腺癌细胞中研究了抑制性AhR-雌激素受体（ER）相互作用的机制。AhR介导的对E2诱导的组织蛋白酶D、pS2、c-fos和热休克蛋白27基因表达的抑制涉及AhR复合物与抑制性五核苷酸（GCGTG）二恶英反应元件（iDREs）的直接相互作用，导致ER作用所需的结合DNA元件的蛋白质与基础转录机制之间的相互作用被破坏。抑制性AhR-ER相互作用的机制表明，功能性iDREs是某些基因抑制所必需的；然而，结果表明其他相互作用途径也很重要，包括AhR介导的ER蛋白酶体依赖性降解。
