Ah receptor agonists as endocrine disruptors: antiestrogenic activity and mechanisms

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and related compounds induce a b road spectrum of biochemical and toxic responses and disrupt multiple endoc rine pathways. Research in this laboratory has focused on characterizing ar yl hydrocarbon receptor (AhR)-mediated antiestrogenicity in the rodent uter us and mammary and in human breast cancer cells. TCDD inhibits multiple est rogen (E2)-induced responses in these tissues including development or grow th of human mammary and endometrial cancer cells, carcinogen-induced mammar y cancer in rats, and mammary cancer in mice bearing breast cancer cell xen ografts. The mechanisms of AhR-mediated antiestrogenicity are complex; howe ver, studies on the molecular biology of cross-talk between the AhR and est rogen-receptor (ER) signaling pathways have been initiated using several E2 -regulated genes as models. The results indicate that the nuclear AhR compl ex targets specific genomic core inhibitory-dioxin responsive elements (iDR Es) in promoter regions of some E2-responsive target genes to inhibit hormo ne-induced transactivation. The pS2, cathepsin and c-fos genes have functio nal iDREs, whereas the iDRE in the progesterone receptor gene promoter was not functional. Research has also focused on development of AhR-based antie strogens which inhibit mammary tumor development and growth but do not exhi bit prototypical AhR-induced toxic responses. (C) 1998 Elsevier Science Ire land Ltd. All rights reserved.