Estrogen receptor alpha (
ERalpha) has an established role in promoting
breast cancer. Transcriptional activation by
ERalpha is a complex and multistep process, and it is influenced by coactivator and
corepressor proteins that can either positively or negatively modulate
ERalpha-mediated transcriptional activity.
Corepressors are proposed to provide a counterbalance to the
estrogen-induced transactivation, and represent a potential mechanism employed by the cell to regulate hormonal responses. In this review, we present evidence from tissue culture, animal and clinical studies, supporting the hypothesis that
corepressors are crucial regulators of
ERalpha-mediated action, and that their loss could promote
breast cancer development and resistance to endocrine
therapy. We propose that
ERalpha corepressors play an important
biological role by controlling the magnitude of the
estrogen response, mediating
antiestrogen inhibition of
ERalpha, repressing
DNA-bound
ERalpha in the absence of the
ligand, and conferring active repression of
ERalpha-downregulated genes. Different
ERalpha corepressors regulate
steroid receptor activity through a variety of mechanisms, including formation of
multiprotein complexes that are able to affect chromatin remodeling,
histone deacetylation, or basal transcription. Other mechanisms include competition with coactivators, interference with
DNA binding and
ERalpha homodimerization, alteration of
ERalpha stability, sequestration of
ERalpha in the cytoplasm, and effects on RNA processing. Most
ERalpha corepressors can control the receptor's activity through more than one mechanism, and it is possible that the synergy between different pathways cooperates to fully inhibit
ERalpha transcriptional activity, and create an integrated response to a variety of different cellular signaling pathways. We will discuss the role of
corepressors in
tumor suppression and the link they might present between
ERalpha regulation and DNA repair. Finally, we will discuss major challenges in the field and speculate on the exciting findings that await us in the next few years.