**3.1 Regulation of estrogen-responsive genes by ERRs**

Despite their sequence homology (36%) with ERs in the LBD, ERRs do not (or only very weakly) respond to estradiol (E2) and are constitutively active [18–22]. Their LBD interacts with the steroid receptor coactivator 1 (SRC-1) in the absence of any ligand and resumes an active conformation [18]. Since ERRs are identified using DBD of ER and the two receptors share high DBD domain similarities, all three members of the ERR family are able to bind to the half-site hexanucleotide repeat of the classical estrogen response element (ERE) that are recognized by ER [8]. Because of these characteristics of ERRs, earlier studies focused on identifying target genes that are shared by ERR and ER. These studies identified a small handful of genes of which the transcriptions are co-regulated by ERR and ER [23–25]. These genes were associated with clinical outcomes in a COX regression analysis. Among them, pS2, a well-recognized marker for breast cancer was the first common ERR and ER target identified [25]. It was demonstrated that ERRα is a transcriptional activator that interacts with coactivators and binds to EREs in the absence of a ligand in ER+ breast cancers. This ERR induced activity was accredited for the ability of diethylstilbestrol, an ER/ERR antagonist to inhibit pS2 expression in ER- breast cancer cells. Using luciferase reporters in ER+ MCF-7 cells, it was shown that the ERRα competes with ER for binding to ERE and acts as a repressor for the transcription regulation of ER

responsive genes. On the other hand, ERRα acts as a transcription activator in Hela cells when ER and estrogen are not present [13].
