title: The aryl hydrocarbon receptor mediates degradation of estrogen receptor alpha through activation of proteasomes.
abstract: 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and other aryl hydrocarbon receptor (AhR) ligands suppress 17beta-estradiol (E)-induced responses in the rodent uterus and mammary tumors and in human breast cancer cells. Treatment of ZR-75, T47D, and MCF-7 human breast cancer cells with TCDD induces proteasome-dependent degradation of endogenous estrogen receptor alpha (ERalpha). The proteasome inhibitors MG132, PSI, and PSII inhibit the proteasome-dependent effects induced by TCDD, whereas the protease inhibitors EST, calpain inhibitor II, and chloroquine do not affect this response. ERalpha levels in the mouse uterus and breast cancer cells were significantly lower after cotreatment with E plus TCDD than after treatment with E or TCDD alone, and our results indicate that AhR-mediated inhibition of E-induced transactivation is mainly due to limiting levels of ERalpha in cells cotreated with E plus TCDD. TCDD alone or in combination with E increases formation of ubiquitinated forms of ERalpha, and both coimmunoprecipitation and mammalian two-hybrid assays demonstrate that TCDD induces interaction of the AhR with ERalpha in the presence or absence of E. In contrast, E does not induce AhR-ERalpha interactions. Thus, inhibitory AhR-ERalpha cross talk is linked to a novel pathway for degradation of ERalpha in which TCDD initially induces formation of a nuclear AhR complex which coordinately recruits ERalpha and the proteasome complex, resulting in degradation of both receptors.
authors.affiliation: Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX 77843-4466, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Wormke
authors.forename: Matthew
authors.initials: M
authors.lastname: Stoner
authors.forename: Bradley
authors.initials: B
authors.lastname: Saville
authors.forename: Kelcey
authors.initials: K
authors.lastname: Walker
authors.forename: Maen
authors.initials: M
authors.lastname: Abdelrahim
authors.forename: Robert
authors.initials: R
authors.lastname: Burghardt
authors.forename: Stephen
authors.initials: S
authors.lastname: Safe
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D003513:Cycloheximide / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004958:Estradiol / Q000494:pharmacology*; D047628:Estrogen Receptor alpha; D005260:Female; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D046911:Macromolecular Substances; D051379:Mice; D008954:Models, Biological; D009363:Neoplasm Proteins / Q000187:drug effects / Q000378:metabolism; D010447:Peptide Hydrolases / Q000378:metabolism*; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex; D047428:Protein Kinase Inhibitors; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D017434:Protein Structure, Tertiary; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D020239:Receptor Cross-Talk / Q000187:drug effects*; D018336:Receptors, Aryl Hydrocarbon / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D011960:Receptors, Estrogen / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D017384:Sequence Deletion; D015533:Transcriptional Activation / Q000187:drug effects; D014162:Transfection; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D047628:Estrogen Receptor alpha; D005419:Flavonoids; D046911:Macromolecular Substances; D009363:Neoplasm Proteins; D000072317:Polychlorinated Dibenzodioxins; D011480:Protease Inhibitors; D047428:Protein Kinase Inhibitors; D011500:Protein Synthesis Inhibitors; D018336:Receptors, Aryl Hydrocarbon; D011960:Receptors, Estrogen; D011993:Recombinant Fusion Proteins; D025801:Ubiquitin; D004958:Estradiol; D003513:Cycloheximide; D010447:Peptide Hydrolases; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one