Targeting ERα Coregulator Networks to Overcome Endocrine Resistance in ER + Breast Cancer

Breast cancer (BC) is the most commonly diagnosed tumor among women worldwide. Approximately 70% of cases are estrogen receptor-positive (ER+), whose growth is driven by estrogen signaling. Endocrine therapies targeting ER signaling are the common treatment for ER+ disease; however, both intrinsic and acquired endocrine resistance continue to be a major clinical challenge. A growing body of evidence indicates that multiple coregulators influence ER recruitment to its genomic binding sites and tumor growth. Their aberrant expression can promote ligand-independent ER activation and attenuate the effectiveness of ER-targeted therapies. Consequently, targeting ERα coregulators has emerged as a promising therapeutic strategy to overcome endocrine resistance. In this review, we synthesize current evidence defining the roles of ERα coregulators in endocrine resistance, critically assess their therapeutic potential, and provide prioritization guidance for clinical development. A deeper understanding of the molecular mechanisms underpinning endocrine resistance is essential to improve treatment outcomes for patients with ER+ BC.