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

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 (Arnt) 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-oestradiol (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.