Ah receptor agonists as endocrine disruptors: Antiestrogenic activity and mechanisms

S. Safe, F. Wang, W. Porter, R. Duan, A. McDougal

Research output: Contribution to journalArticlepeer-review

209 Scopus citations

Abstract

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and related compounds induce a broad spectrum of biochemical and toxic responses and disrupt multiple endocrine pathways. Research in this laboratory has focused on characterizing aryl hydrocarbon receptor (AhR)-mediated antiestrogenicity in the rodent uterus and mammary and in human breast cancer cells. TCDD inhibits multiple estrogen (E2)-induced responses in these tissues including development or growth of human mammary and endometrial cancer cells, carcinogen-induced mammary cancer in rats, and mammary cancer in mice bearing breast cancer cell xenografts. The mechanisms of AhR-mediated antiestrogenicity are complex; however, studies on the molecular biology of cross-talk between the AhR and estrogen-receptor (ER) signaling pathways have been initiated using several E2-regulated genes as models. The results indicate that the nuclear AhR complex targets specific genomic core inhibitory dioxin responsive elements (iDREs) in promoter regions of some E2-responsive target genes to inhibit hormone-induced transactivation. The pS2, cathepsin and c-fos genes have functional iDREs, whereas the iDRE in the progesterone receptor gene promoter was not functional. Research has also focused on development of AhR-based antiestrogens which inhibit mammary tumor development and growth but do not exhibit prototypical AhR-induced toxic responses. Copyright (C) 1998 Elsevier Science Ireland Ltd. All rights reserved.

Original languageEnglish (US)
Pages (from-to)343-347
Number of pages5
JournalToxicology Letters
Volume102-103
DOIs
StatePublished - Dec 28 1998

Keywords

  • 2,3,7,8-Tetrachlorodibenzo-p-dioxin
  • Ah receptor
  • Antiestrogens
  • Antitumor agents
  • Endocrine disruptors

ASJC Scopus subject areas

  • Toxicology

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