Estrogen receptor corepressors -- a role in human breast cancer?

Abstract

Estrogen receptor α (ERα) has an established role in promoting breast cancer. Transcriptional activation by ERα is a complex and multistep process, and it is influenced by coactivator and corepressor proteins that can either positively or negatively modulate ERα-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 ERα-mediated action, and that their loss could promote breast cancer development and resistance to endocrine therapy. We propose that ERα corepressors play an important biological role by controlling the magnitude of the estrogen response, mediating antiestrogen inhibition of ERα, repressing DNA-bound ERα in the absence of the ligand, and conferring active repression of ERα-downregulated genes. Different ERα 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 ERα homodimerization, alteration of ERα stability, sequestration of ERα in the cytoplasm, and effects on RNA processing. Most ERα 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 ERα 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 ERα 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.

Identification of estrogen-responsive genes based on the DNA binding properties of estrogen receptors using high-throughput sequencing technology

“…When the receptor is occupied with an antagonist or free from ligands, it is associated with a transcriptional corepressor that represses transcription [14] . Corepressors form a protein complex with histone deacetylases and exert their function to maintain a rigid histone structure.…”

RETRACTED ARTICLE: Regulation of estrogen receptor signaling in breast carcinogenesis and breast cancer therapy

“…The corepressors counterbalance the actions of coactivators to orchestrate the magnitude of E2 responses, which leads to the inhibition of ERα target gene expression. Therefore, loss of ERα corepressors promotes breast cancer [187]. Many corepressors of ERα have been identified, and their activities associated with breast cancer are characterized.…”

Changes in subcellular localisation of MI-ER1α, a novel oestrogen receptor-α interacting protein, is associated with breast cancer progression

“…Traditionally, corepressors bind unliganded NRs, whereas coactivators bind liganded NRs; however, ERa is distinct from other NRs in this regard (Dobrzycka et al, 2003). For example, the classic corepressors, NCoR (Horlein et al, 1995) and SMRT (Chen and Evans, 1995), interact only with antagonist-bound ERa, whereas LCoR interacts with ERa only in the presence of oestrogen (Fernandes et al, 2003).…”