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Molecular Mechanism of Inhibitory Aryl Hydrocarbon Receptor—Estrogen Receptor/Sp1 Cross Talk in Breast Cancer Cells

Department of Veterinary Physiology and Pharmacology (S.K., S.S.), Department of Veterinary Integrated Biology (R.B., R.B.), Texas A&M University, College Station, Texas 77843; and Institute of Biosciences and Technology (S.L., S.S.), Texas A&M University System Health Science Center, Houston, Texas 77030

Address all correspondence and requests for reprints to: Stephen Safe, Department of Veterinary Physiology and Pharmacology, Texas A&M University, 4466 TAMU, College Station, Texas 77843-4466. E-mail: ssafe{at}cvm.tamu.edu.

The trifunctional carbamoylphosphate synthetase/aspartate transcarbamyltransferase/dihydroorotase (CAD) gene is hormone responsive in MCF-7 and ZR-75 breast cancer cells, and this response is inhibited by the aryl hydrocarbon receptor (AhR) agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Estrogen-dependent induction of CAD mRNA and reporter gene activity in cells transfected with constructs (pCAD) containing hormone-responsive GC-rich CAD promoter inserts involves estrogen receptor (ER)/Sp1 interactions with these proximal GC-rich motifs. TCDD also inhibits hormone-induced transactivation in MCF-7 and ZR-75 cells transfected with pCAD constructs. The mechanism of inhibitory AhR-ER/Sp1 cross talk was further investigated by chromatin immunoprecipitation (ChIP), and the results show that ER/Sp1 and the AhR are constitutively bound to the CAD gene promoter and only minor changes are observed after treatment with 17ß-estradiol, TCDD, or their combination. However, examination of interactions of these transcription factors by fluorescence resonance energy transfer shows that E2 enhances ER-Sp1 interactions, whereas cotreatment with TCDD significantly decreases interaction of these proteins. These results suggest that inhibitory AhR-ER/Sp1 cross talk is due, in part, to enhanced association of AhR and ER (also determined by fluorescence resonance energy transfer), which coordinately dissociates ER and Sp1 and decreases ER/Sp1-mediated transactivation, whereas remaining associated with the CAD promoter. This represents a novel interaction between two ligand activated receptors where one receptor inhibits activation of the second receptor.

NURSA Molecule Pages Link:

Nuclear Receptors:   ERα

Ligands:   17β-Estradiol  |  Fulvestrant

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