Aryl hydrocarbon receptor-independent activation of estrogen receptor-dependent transcription by 3-methylcholanthrene

Toxicol Appl Pharmacol. 2006 Jun 1;213(2):87-97. doi: 10.1016/j.taap.2005.09.011. Epub 2005 Oct 27.

Abstract

Aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that stimulates transcription directed by xenobiotic response elements upstream of target genes. Recently, AhR ligands were reported to induce formation of an AhR-estrogen receptor (ER) complex, which can bind to estrogen response elements (EREs) and stimulate transcription of ER target genes. Presently, we investigate the effect of the AhR ligands 3-methylcholanthrene (3MC), 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and 3,3',4,4',5-pentachlorobiphenyl (BZ126) on ERE-regulated luciferase reporter activity and endogenous ER target gene expression. In MCF-7 human breast cancer cells, 3MC induced transcription of ER reporter genes containing native promoter sequences of the ER-responsive genes complement 3 and pS2 and heterologous promoters regulated by isolated EREs. Dose-response studies revealed that the concentration of 3MC required to half-maximally activate transcription (EC(50)) was >100-fold higher for an ER reporter (27-57 muM) than for an AhR reporter (86-250 nM) in both MCF-7 cells and in human endometrial cancer Ishikawa cells. 3MC also stimulated expression of the endogenous ER target genes amphiregulin, cathepsin D and progesterone receptor, albeit to a much lower extent than was achieved following stimulation with 17beta-estradiol. In Ishikawa cells, 3MC, but not BZ126 or TCDD, stimulated ERalpha-dependent reporter activity but did not induce expression of endogenous ER target genes. Finally, studies carried out in the AhR-positive rat hepatoma cell line 5L and the AhR-deficient variant BP8 demonstrated that ER reporter activity could be induced by 3MC in a manner that was independent of AhR and thus distinct from the AhR-ER 'hijacking' mechanism described recently. 3MC may thus elicit estrogenic activity by multiple mechanisms.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Breast Neoplasms / metabolism
  • Cell Line, Tumor
  • Dose-Response Relationship, Drug
  • Endometrial Neoplasms / metabolism
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism
  • Estrogen Receptor alpha / genetics
  • Estrogen Receptor alpha / metabolism*
  • Female
  • Gene Expression Regulation / drug effects*
  • Genes, Reporter / drug effects
  • Genes, Reporter / physiology
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism
  • Humans
  • Ligands
  • Liver Neoplasms / metabolism
  • Methylcholanthrene / pharmacology*
  • Polychlorinated Biphenyls / pharmacology
  • Polychlorinated Dibenzodioxins / pharmacology
  • Rats
  • Receptors, Aryl Hydrocarbon / agonists*
  • Receptors, Aryl Hydrocarbon / metabolism
  • Selective Estrogen Receptor Modulators / pharmacology*
  • Transcriptional Activation / drug effects*
  • Transcriptional Activation / physiology

Substances

  • Estrogen Receptor alpha
  • Ligands
  • Polychlorinated Dibenzodioxins
  • Receptors, Aryl Hydrocarbon
  • Selective Estrogen Receptor Modulators
  • Methylcholanthrene
  • Polychlorinated Biphenyls
  • 3,4,5,3',4'-pentachlorobiphenyl