The aryl hydrocarbon receptor (AHR)/AHR nuclear translocator (ARNT) heterodimer interacts with naturally occurring estrogen response elements

To determine the molecular mechanisms underlying the ''cross talk" between the activity of 2,3,7,8-tetra-chlorodibenzo-p-dioxin (TCDD), which binds to arylhydrocarbon receptor (AHR) and estradiol (E-2)-liganded estrogen recep tor (ER), we first examined the initial step of estrogen action, ligand bin ding to ER. None of the AHR ligands tested, i.e. TCDD, benzo[a]pyrene, 3,3' ,4,4',5-pentachlorobiphenyl, beta-naphthoflavone, or alpha-naphthoflavone, bound to ER alpha. We report the first examination of TCDD interaction with ER beta:TCDD did not displace E-2 from ER beta. We then examined a second possible mechanism, i.e. direct inhibition of ER alpha binding to estrogen response elements (EREs) by the AHR/AHR nuclear translocator (ARNT) complex . The AHR/ARNT heterodimer did not bind either a full or half-site ERE. How ever, AHR/ARNT bound specifically to oligomers containing naturally occurri ng EREs derived from the human c-fos, pS2, and progesterone receptor (PR) g ene promoters that include xenobiotic response element (XRE)-like sequences . In contrast, neither purified E-2-liganded-ER from calf uterus or recombi nant human ER alpha bound a consensus XRE. TCDD inhibited E-2-activated rep orter gene activity from a consensus ERE and from EREs in the pS2, PR, and Fos genes in transiently transfected MCF-7 human breast cancer cells. Howev er, this inhibition was not reciprocal since E-2 did not inhibit TCDD-stimu lated luciferase activity from the CYP1A1 promoter in transiently transfect ed MCF-7 or human endometrial carcinoma HEC-1A cells. We propose that at le ast part of the mechanism by which the AHR/ARNT complex inhibits estrogen a ction is by competitively inhibiting ERa binding to imperfect ERE sites, ad jacent to or overlapping XREs. (C) 1999 Elsevier Science Ireland Ltd. All r ights reserved.