Estrogen-related receptors as emerging targets in cancer and metabolic disorders

While estrogen receptor (ER)-targeted therapeutics have clearly been a success in the treatment of breast cancer, the orphan estrogen-related receptors (ERRS) represent novel targets for future development. The ERRS, comprising ERR alpha, ERR beta and ERR gamma, bind and regulate transcription via estrogen response elements (EREs) and extended ERE half-sites termed ERR response elements (ERREs), but do not bind endogenous estrogens. The emerging role of ERR alpha and ERR gamma in modulating estrogen responsiveness, substituting for ER activities, and serving as prognosticators in breast and other cancers is providing an impetus for the identification of compounds which target these proteins. Moreover, ERR alpha plays a role in energy homeostasis and will likely be targeted for the treatment of metabolic disorders. Multiple classes of synthetic ligands have already been identified. The phytoestrogens genistein, daidzein, biochanin A and 6,3'4'-tryhydroxyflavone have been reported as ERR alpha agonists. The phenolic acyl hydrazones GSK4716 and GSK9089 act as selective agonists of ERR beta and ERR gamma. The organochlorine pesticides toxaphene and chlordane, and the synthetic compound XCT790 antagonize ERR alpha. The synthetic estrogen diethylstilbestrol antagonizes all three ERRS. The selective estrogen receptor modulators 4-hydroxytamoxifen and 4-hydroxytoremifene antagonize ERR gamma. The rational development of synthetic ligands for the ERRS may soon provide new agents to supplement the repertoire of antihormonal therapies to combat breast cancer. Moreover, expression of ERRS in other cancers and metabolic disorders may provide a targeted treatment strategy for these patients as well.