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

3-Methylcholanthrene (3MC) is an aryl hydrocarbon receptor (AhR) agonist, and it has been reported that 3MC induces estrogenic activity through AhR-estrogen receptor A (ERA) interactions. In this study, we used 3MC and 3,3V,4,4V,5pentachlorobiphenyl (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 ERA but were not affected by the small inhibitory RNA for AhR. These results suggest that 3MC and PCB directly activate ERA, and this was confirmed in a competitive ERA binding assay and in a fluorescence resonance energy transfer experiment in which PCB and 3MC induced CFP-ERA/YFP-ERA interactions. In a chromatin immunoprecipitation assay, PCB and 3MC enhanced ERA (but not AhR) association with the estrogenresponsive 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 ERA-dependent transactivation and extend the number of ligands that activate both AhR and ERA. (Cancer Res 2006; 66(4): 2459-67)