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

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.