Molecular Pathways: The Metabolic Regulator Estrogen-Related Receptor α as a Therapeutic Target in Cancer

The estrogen-related receptor alpha (ERR alpha) is an orphan member of the nuclear receptor superfamily of transcription factors whose activity is regulated by the expression level and/or activity of its obligate coregulators, peroxisome proliferator-activated receptor gamma coactivator-1 alpha and beta (PGC-1 alpha or PGC-1 beta). Under normal physiologic conditions, and in responding to different environmental stimuli, the ERR alpha/PGC-1 complex is involved in regulating metabolic homeostasis under conditions of high energy demand in brown adipocytes, proliferating T cells, and muscle. Interestingly, increased expression and activity of the ERR alpha/PGC-1 axis has also been shown to correlate with unfavorable clinical outcomes in both breast and ovarian tumors. The observation that ERR alpha activity is manifest in all breast tumor subtypes with particularly high activity being evident in ER alpha-negative, HER2-positive, and triple-negative breast cancers has raised significant interest in targeting this receptor for the treatment of those breast cancers for which therapeutic options are limited. Clin Cancer Res; 18(22); 6089-95. (C)2012 AACR.