Estrogen-related receptor α1 actively antagonizes estrogen receptor-regulated transcription in MCF-7 mammary cells

Abstract

The estrogen-related receptor α (ERRα) is an orphan member of the nuclear receptor superfamily. We show that the major isoform of the human ERRα gene, ERRαl, can sequence-specifically bind a consensus palindromic estrogen response element (ERE) and directly compete with estrogen receptor α (ERα) for binding. ERRαl activates or represses ERE-regulated transcription in a cell type-dependent manner, repressing in ER-positive MCF-7 cells while activating in ER-negative HeLa cells. Thus, ERRαl can function both as a modulator of estrogen responsiveness and as an estrogen-independent activator. Repression likely occurs in the absence of exogenous ligand since charcoal treatment of the serum had no effect on silencing activity. Mutational analysis revealed that repression is not simply the result of competition between ERα and ERRαl for binding to the DNA. Rather, it also requires the presence of sequences within the carboxyl-terminal E/F domain of ERRαl. Thus, ERRαl can function as either an active repressor or a constitutive activator of ERE-dependent transcription. We hypothesize that ERRαl can play a critical role in the etiology of some breast cancers, thereby providing a novel therapeutic target in their treatment.