Mechanisms of Endocrine Resistance in Hormone Receptor–Positive Breast Cancer: An Integrated Genomic and Translational Review

Hormone receptor–positive (HR⁺) breast cancer often develops resistance to endocrine therapy (ET), limiting long-term efficacy. This integrated review synthesizes genomic and translational evidence to delineate the multifactorial nature of endocrine resistance. Key mechanisms include ESR1 ligand-binding domain mutations, amplifications, and fusions, which sustain estrogen receptor signaling under therapeutic pressure. Compensatory activation of receptor tyrosine kinase (e.g., HER2, FGFR) and PI3K/AKT/mTOR pathways provides alternative survival routes. Furthermore, epigenetic reprogramming, cell-cycle deregulation, tumor heterogeneity, and microenvironmental influences contribute to both primary (de novo) and acquired resistance. While ESR1 mutations are hallmarks of acquired resistance following aromatase inhibitors, primary resistance is frequently associated with TP53 mutations and distinct DNA methylation patterns. The review highlights emerging biomarkers and therapeutic strategies, including ESR1 genotyping to guide SERD/SERCA use, and rational combinations targeting CDK4/6, PI3K, and epigenetic regulators. Future directions emphasize longitudinal multi-omic profiling, functional annotation of resistance drivers, and integration of microenvironmental cues to develop adaptive, biomarker-driven therapies that preempt resistance and improve outcomes in HR⁺ breast cancer.