Development of selective aryl hydrocarbon receptor modulators for treatment of breast cancer

S. Safe, C. Qin, A. McDougal

Research output: Contribution to journalReview article

59 Scopus citations

Abstract

The aryl hydrocarbon receptor (AhR) is a basic helix-loop-helix DNA-binding protein that forms a transcriptionally-active heterodimer with the AhR nuclear translocator (Amt) protein. The nuclear AhR complex is a ligand-induced transcription factor and the environmental toxicant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a high affinity ligand for the AhR. TCDD induces a diverse spectrum of tissue, sex- and species-specific biochemical and toxic responses in Ah-responsive cells/tissues including the inhibition of 17β-oesrtadiol (E2)-induced gene expression in the rodent uterus and mammary and in human breast cancer cell lines. TCDD also inhibits spontaneous and carcinogen-induced mammary tumour formation and growth in rodent models. Research in this laboratory has utilised the AhR as a target for developing anticancer drugs for treatment of breast cancer and two different structural classes of selective AhR modulators (SAhRMs) have been developed. Alternate-substituted (1,3,6,8- and 2,4,6,8-) alkyl polychlorinated dibenzofurans (PCDFs) and substituted diindolylmethanes (DIMs) bind the AhR and induce a pattern of AhR-oestrogen receptor (ER) inhibitory cross-talk similar to that observed for TCDD including inhibition of mammary tumour growth at doses < 1.0 mg/kg/day. In contrast, effective doses of these compounds do not induce hepatic CYP1A1-dependent activity or other AhR-mediated toxic responses induced by TCDD. These results indicate that SAhRMs may be an important new class of drugs for clinical treatment of breast cancer via AhR-ER inhibitory cross-talk.

Original languageEnglish (US)
Pages (from-to)1385-1396
Number of pages12
JournalExpert Opinion on Investigational Drugs
Volume8
Issue number9
DOIs
StatePublished - 1999

Keywords

  • Ah receptor-oestrogen receptor cross-talk
  • Alkyl PCDFs
  • Anti-oestrogenicity
  • Antitumourigenicity
  • Breast cancer
  • Selective aryl hydrocarbon receptor modulators (SAhRMs)

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

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