Molecular Mechanisms and Epigenetic Regulation in Estrogen Receptor-Positive Breast Cancer: Implications for Therapy and Resistance

Estrogen receptor-positive (ER+) breast cancer represents the majority of breast cancer cases and is characterized by complex molecular heterogeneity shaped by genetic and epigenetic factors. Epigenetic regulation—including DNA methylation, histone modifications, and non-coding RNAs—plays a pivotal role in modulating estrogen receptor signaling, influencing tumor progression, therapeutic response, and resistance mechanisms. Environmental exposures, lifestyle factors, and aging contribute to dynamic epigenetic alterations that affect gene expression and endocrine therapy efficacy. Recent advances in understanding ER biology reveal the significance of pioneer transcription factors and intratumoral heterogeneity in driving diverse clinical outcomes. Therapeutically, novel endocrine agents such as oral selective estrogen receptor degraders (SERDs) and selective estrogen receptor covalent antagonists (SERCAs) show promise in overcoming resistance, while combination strategies incorporating CDK4/6 and PI3K/AKT/mTOR inhibitors improve clinical benefit. Epigenetic therapies, including HDAC and DNMT inhibitors, alongside emerging CRISPR-based epigenome editing tools, offer innovative avenues to reverse resistance, though challenges remain in toxicity management and biomarker development. Liquid biopsies and multi-omics integration enhance real-time disease monitoring and precision medicine approaches. This review synthesizes current molecular insights and epigenetic mechanisms in ER+ breast cancer, emphasizing their implications for therapeutic innovation and overcoming endocrine resistance.