Chlorinated hydrocarbons: estrogens and antiestrogens

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and related compounds bind to the intracellular aryl hydrocarbon (Ah) receptor and induce a diverse spectrum of biochemical and toxic responses. Ah receptor agonists also modulate several endocrine pathways, and research in several laboratories has shown that TCDD and related compounds inhibit estrogen (E2)-induced responses in the rodent mammary and uterus and in human breast cancer cell lines. The mechanisms of interaction between the TCDD- and E2-induced signaling pathways are complex and some of the inhibitory effects may be related to 5′-flanking inhibitory-dioxin responsive elements (i-DREs) in target genes. The antiestrogenic and antitumorigenic activity of Ah receptor agonists has been used to prepare a series of relatively non-toxic alkyl polychlorinated dibenzofurans which have clinical potential for treatment of mammary cancer.