Chalcones are antagonists of estrogen-related receptors

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Results from this and other laboratories have found that estrogen-related receptor α (ERRα) can activate gene transcription in a constitutive manner. Our results from site-directed mutagenesis experiments have revealed that Phe-232 (analogous to Ala-350 in ERα) is responsible for the constitutive activity of ERRα. In addition, our laboratory has previously found that ERRα has a positive regulatory effect on aromatase expression in breast cancer cells. An investigation was initiated in our laboratory to search for environmental chemicals that can modulate aromatase expression by interacting with this receptor. We have found that two organochlorine pesticides, toxaphene and chlordane, are antagonists of ERRα. In addition, through virtual ligand screening, we have determined that three isoflavones (genistein, daidzein and biochanin A) and one flavone (6,3’, 4’-trihydroxyflavone) behaved as agonists of ERRs. Our receptor functional analysis further indicated that an effective agonist should be a molecule without bulky substituents in the middle and with a pair of lined-up hydrogen bond forming groups at the ends. These phytoestrogens induced the activity of ERRα at concentrations that are comparable with the activation of ERα and ERβ. We have recently extended our ligand analysis involving other phytochemicals. We have learned that several chalcones can act as agonists/antagonists of ERRα. We confirmed the interaction of chalcones with three isoforms of ERR (ERRα, ERRβ, and ERRγ) and ERα by mammalian transfection experiment, mammalian two-hybrid assay, and [³H] genistein competitive binding assay. Among the antagonists of ERRs identified, only one chalcone was shown to be an antagonist of ERα. Current efforts are to determine the structure-activity relationship for the interaction of these chalcones with ERRα. In addition to modulate aromatase expression, ERRα has been found to play a role in lipogenesis in adipose tissues, atherosclerosis and the development of diabetes. Our study will generate important information as to how environmental chemicals that act as ligands of ERRα, modify these documented functions of this receptor.