Mechanism of action and development of selective aryl hydrocarbon receptor modulators for treatment of hormone-dependent cancers (Review)

Int J Oncol. 2002 Jun;20(6):1123-8.


Ligand-activated receptors are extensively used as targets for developing tissue-selective drugs for treatment of multiple diseases including cancers. The aryl hydrocarbon receptor (AhR) is a basic helix-loop-helix transcription factor that binds both synthetic chemicals such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and naturally-occurring phytochemicals, sterols and heme breakdown products. The high affinity ligand TCDD induces several AhR-mediated changes in gene expression, tissue/species-specific toxicities, and both tumorigenic and anticarcinogenic responses including inhibition of estrogen-dependent mammary and uterine tumor formation and growth. Research in this laboratory has demonstrated that TCDD inhibits E2-induced responses in the rodent uterus and mammary tumors (growth inhibition) and in breast and endometrial cancer cell lines through complex inhibitory AhR-estrogen receptor (ER) crosstalk. 6-Alkyl-1,3,8-trichlorodibenzofurans and substituted diindolylmethanes represent two structural classes of selective AhR modulators (SAhRMs). These compounds are relatively non-toxic and inhibit ER-positive and ER-negative mammary tumor growth, and synergize with tamoxifen to inhibit breast cancer growth and block tamoxifen-induced estrogenic activity in the uterus. Preliminary studies also indicate that SAhRMs inhibit prostate cancer cell growth, and there is evidence for inhibitory AhR-androgen receptor crosstalk. SAhRMs represent a novel class of drugs for treatment of hormone-dependent cancers, and combined therapies of SAhRMs with tamoxifen and other selective ER modulators (SERMs) provides a new approach for treating women with breast cancer.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Breast Neoplasms / drug therapy
  • Female
  • Humans
  • Male
  • Neoplasms, Hormone-Dependent / drug therapy*
  • Polychlorinated Dibenzodioxins / pharmacology
  • Receptors, Aryl Hydrocarbon / drug effects*
  • Receptors, Aryl Hydrocarbon / physiology
  • Receptors, Estrogen / analysis
  • Receptors, Estrogen / antagonists & inhibitors
  • Receptors, Estrogen / drug effects
  • Selective Estrogen Receptor Modulators / therapeutic use


  • Polychlorinated Dibenzodioxins
  • Receptors, Aryl Hydrocarbon
  • Receptors, Estrogen
  • Selective Estrogen Receptor Modulators