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Molecular and Cellular Biology, March 2003, p. 1843-1855, Vol. 23, No. 6
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.6.1843-1855.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

The Aryl Hydrocarbon Receptor Mediates Degradation of Estrogen Receptor {alpha} through Activation of Proteasomes

Mark Wormke,1 Matthew Stoner,1 Bradley Saville,1 Kelcey Walker,1 Maen Abdelrahim,1 Robert Burghardt,2 and Stephen Safe1*

Department of Veterinary Physiology and Pharmacology,1 Department of Veterinary Anatomy and Public Health, Texas A&M University, College Station, Texas2

Received 25 April 2002/ Returned for modification 25 June 2002/ Accepted 18 December 2002

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and other aryl hydrocarbon receptor (AhR) ligands suppress 17ß-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} (ER{alpha}). 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. ER{alpha} 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 ER{alpha} in cells cotreated with E plus TCDD. TCDD alone or in combination with E increases formation of ubiquitinated forms of ER{alpha}, and both coimmunoprecipitation and mammalian two-hybrid assays demonstrate that TCDD induces interaction of the AhR with ER{alpha} in the presence or absence of E. In contrast, E does not induce AhR-ER{alpha} interactions. Thus, inhibitory AhR-ER{alpha} cross talk is linked to a novel pathway for degradation of ER{alpha} in which TCDD initially induces formation of a nuclear AhR complex which coordinately recruits ER{alpha} and the proteasome complex, resulting in degradation of both receptors.

* Corresponding author. Mailing address: Department of Veterinary Physiology and Pharmacology, Texas A&M University, 4466 TAMU, College Station, TX 77843-4466. Phone: (979) 845-5988. Fax: (979) 862-4929. E-mail: ssafe{at}cvm.tamu.edu.

Molecular and Cellular Biology, March 2003, p. 1843-1855, Vol. 23, No. 6
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.6.1843-1855.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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