Role of estrogen receptor α transcriptional coregulators in tamoxifen resistance in breast cancer

Tamoxifen is the endocrine agent most commonly used at all stages of breast cancer. Estrogen receptor (ER) α, which belongs to the superfamily of nuclear receptors, has been used to identify breast cancer patients who are likely to respond to tamoxifen, but resistance nonetheless occurs in 30–50% of treated ERα-positive breast cancer patients.The antiproliferative activity of tamoxifen, relying primarily on its ability to compete with estrogen for the ERα ligand binding site in breast tumor tissue, hypotheses forwarded to explain treatment failure include: (1) the existence of a second estrogen receptor (ERβ), (2) an imbalance in estrogen biosynthesis and catabolism, (3) altered bioavailability of tamoxifen, (4) altered cellular trafficking of ERα, (5) non genomic effects of ERα, directly interacting with several signal transduction pathways, and (6) transcriptional dysregulation of ERα target genes, which may involve both genomic (ERE alteration) and non genomic alterations.A first non genomic alteration involves the regulation of ERα activity by its phosphorylation mediated by growth factors-kinases signaling pathways. A second non genomic alteration, which is the purpose of this review, involves regulatory factors (coregulators) known as coactivators and corepressors, which activate (or repress) the transcription of ERα-responsive genes. The regulation process involves both chromatin remodeling and ERα interaction with the transcriptional machinery. Thus, dysregulated expression (coactivator overexpression or corepressor underexpression) and/or mutation of these coregulators is thought to impair the action of tamoxifen.Many altered pathways may account for tamoxifen resistance which may be best studied by multigene approaches.