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3-Methylcholanthrene and Other Aryl Hydrocarbon Receptor Agonists Directly Activate Estrogen Receptor

¹ Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, Texas; ² Fox Chase Cancer Center, Philadelphia, Pennsylvania; and ³ Department of Veterinary Physiology and Pharmacology, and ⁴ Department of Veterinary Integrated Biosciences, Texas A&M University, College Station, Texas

Requests for reprints: Stephen Safe, 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.

3-Methylcholanthrene (3MC) is an aryl hydrocarbon receptor (AhR) agonist, and it has been reported that 3MC induces estrogenic activity through AhR-estrogen receptor (ER) interactions. In this study, we used 3MC and 3,3',4,4',5-pentachlorobiphenyl (PCB) as prototypical AhR ligands, and both compounds activated estrogen-responsive reporter genes/gene products (cathepsin D) in MCF-7 breast cancer cells. The estrogenic responses induced by these AhR ligands were inhibited by the antiestrogen ICI 182780 and by the transfection of a small inhibitory RNA for ER but were not affected by the small inhibitory RNA for AhR. These results suggest that 3MC and PCB directly activate ER, and this was confirmed in a competitive ER binding assay and in a fluorescence resonance energy transfer experiment in which PCB and 3MC induced CFP-ER/YFP-ER interactions. In a chromatin immunoprecipitation assay, PCB and 3MC enhanced ER (but not AhR) association with the estrogen-responsive region of the pS2 gene promoter. Moreover, in AhR knockout mice, 3MC increased uterine weights and induced expression of cyclin D1 mRNA levels. These results show that PCB and 3MC directly activate ER-dependent transactivation and extend the number of ligands that activate both AhR and ER. (Cancer Res 2006; 66(4): 2459-67)

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