Estrogen-related receptor alpha: an orphan finds a family

Nuclear receptors (NRs) are well accepted as critical mediators in many aspects of breast cancer pathogenesis. Molecular cloning of estrogen receptor alpha (ERα) has demonstrated how molecular targeting of specific domains of a single protein can improve outcomes. Molecular cloning techniques have revealed receptors related to ERα, including the 'estrogen-related receptor' (ERR) family.Recent prognostic studies have demonstrated that overexpression of one of these family members, ERRα, is associated with a poor outcome in patients with ER- breast cancer [1], yet the transcriptional regulation of the orphan receptor ERRα is still not well known. Overexpression of ERRα has been shown to be associated with elevated human epidermal growth factor 2 (HER2) expression [2], and ERRα can interact with the co-regulators PGC-1 α and β (peroxisome proliferator-activated gamma co-activator-1 alpha and beta) [3,4] in addition to a number of p160 co-activators [5,6]. Interestingly, ERRα displays distinct subtype transcriptional activation that is not similarly identified by ER [7]. Unlike ERα, which has been targeted by ligand deprivation (oophorectomy and aromatase inhibitors) and selective estrogen receptor modulators (tamoxifen and fulvestrant), ERRα has no known ligand and therefore is not amenable to drug inhibition in the same fashion.If ERRα regulates breast cancer cells, then we need to understand its mechanism of action. Since there are no known ways to target ERRα+ ER- breast cancers, molecular techniques could be used (a) to gain an understanding of how ERRα modulates gene expression in breast cancer subtypes [8-11] and (b) to develop potential therapeutic approaches to target ERRα-driven tumors [12].Chang and colleagues [12] created normal human mammary epithelial cell lines overexpressing ERRα to better understand its transcriptional targets. Since no ligand exists for ERRα, overexpression of the well-characterized co-regulator of ERRα, PGC-1α, was used to activate tr