Role of estrogen receptor α in the regulation of breast cancer progression: signaling pathways and therapeutic implications.

Abstract

Estrogen receptor alpha (ERα) is central to breast-cancer initiation, progression, and endocrine resistance. This narrative review uses a transparent, non-systematic search of peer-reviewed English-language literature published from 2017 through 2025 to integrate ERα structure and isoforms, genomic and non-genomic signaling, post-translational regulation, tumor-microenvironment interactions, heterogeneity, and therapeutic development. The synthesis distinguishes mechanistic, preclinical, and clinical evidence and highlights areas of uncertainty. ESR1 ligand-binding-domain mutations are rare in untreated primary disease but are enriched after endocrine selection in metastatic disease; emerging oral SERDs, ER-directed PROTACs, and biomarker-matched pathway combinations show heterogeneous results across overall and molecularly defined populations. ER-low disease remains a clinically important category requiring confirmation of pathology, integration of tumor biology and disease setting, and individualized use of endocrine and chemotherapy-based strategies. Overall, therapeutic progress increasingly depends on matching ERα-directed interventions to dynamic biomarkers, resistance mechanisms, treatment history, and tolerability rather than assuming uniform benefit across ER-positive disease.