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 (E2)-liganded estrogen receptor (ER), we first examined the initial step of estrogen action, ligand binding to ER. None of the AHR ligands tested, i.e. TCDD, benzo[a]pyrene, 3,3',4,4',5-pentachlorobiphenyl, β-naphthoflavone, or α-naphthoflavone, bound to ERα. We report the first examination of TCDD interaction with ERβ: TCDD did not displace E2 from ERβ. We then examined a second possible mechanism, i.e. direct inhibition of ERα 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. However, AHR/ARNT bound specifically to oligomers containing naturally occurring EREs derived from the human c-fos, pS2, and progesterone receptor (PR) gene promoters that include xenobiotic response element (XRE)-like sequences. In contrast, neither purified E2-liganded-ER from calf uterus or recombinant human ERα bound a consensus XRE. TCDD inhibited E2-activated reporter 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. However, this inhibition was not reciprocal since E2 did not inhibit TCDD-stimulated luciferase activity from the CYP1A1 promoter in transiently transfected MCF-7 or human endometrial carcinoma HEC-1A cells. We propose that at least part of the mechanism by which the AHR/ARNT complex inhibits estrogen action is by competitively inhibiting ERα binding to imperfect ERE sites, adjacent to or overlapping XREs. Copyright (C) 1999 Elsevier Science Ireland Ltd.
|Number of pages||15|
|Journal||Molecular and Cellular Endocrinology|
|State||Published - Nov 25 1999|
Bibliographical noteFunding Information:
We thank Dr K. Cam Faulkner for his assistance in subcloning ERβ. We thank Bethany F. Silver, Cristi H. Brockway, and Sheetal J. Mehta for preparation of the plasmids used in transient transfection assays and for their assistance in β-gal and luciferase assays. We thank the following investigators for sharing plasmids and antisera with us: Dr C.A. Bradfield, Dr J.E. Mertz, Dr R.S. Pollenz, Dr R.A. Prough, and Dr R.H. Tukey. We thank Dr B.J. Clark and Dr R.A. Prough for their comments on this manuscript. Supported by NIH R01 DK 53220, N.I.E.H.S. 1P20 ES06832-12, a University of Louisville School of Medicine Research Award, and Veterans Administration Center for the Study of Environmental Hazards to Reproductive Health Grant 0006, Department of Veterans Affairs Medical Center, Louisville, KY to C.M.K. and in part by the University of Kentucky Medical Center Research Fund Grant #847 and N.I.E.H.S. R29 ES08088 to H.I.S.
- Aryl hydrocarbon receptor
- Estrogen receptor
- Estrogen response element
- Xenobiotic response element
ASJC Scopus subject areas
- Molecular Biology