Targeting Aromatase and HDACs in Hormone Receptor-Positive Breast Cancer: Molecular Interplay, Endocrine Resistance and Therapeutic Opportunities.

Breast cancer is the most frequently diagnosed malignancy in women, and hormone receptor-positive disease represents its predominant subtype. Aromatase inhibitors (AIs) are a cornerstone of endocrine therapy, particularly in postmenopausal patients, but their long-term efficacy is frequently limited by intrinsic or acquired resistance. Increasing evidence indicates that epigenetic dysregulation, especially aberrant histone deacetylase (HDAC) activity, contributes to altered estrogen receptor signaling, transcriptional plasticity, activation of compensatory survival pathways, and endocrine treatment failure. This narrative review examines the biological and therapeutic interplay between aromatase and HDACs in breast cancer, integrating evidence from mechanistic studies, in vitro models, preclinical experiments, and clinical trials. HDAC inhibition may restore endocrine sensitivity by modifying chromatin accessibility, reactivating estrogen-responsive and tumor-suppressor genes, suppressing adaptive pathways such as HER2, NF-κB, and PI3K/AKT/mTOR signaling, and promoting cell-cycle arrest and apoptosis. Preclinical studies support synergistic or sensitizing effects of combined AI-HDAC inhibition, while clinical trials with entinostat, tucidinostat, panobinostat, and exemestane- or letrozole-based regimens have produced heterogeneous results. These findings suggest that endocrine-epigenetic combinations may benefit selected patients rather than represent an universally effective strategy. Future clinical translation will require improved HDAC selectivity, optimized dosing, toxicity management, and validation of predictive biomarkers enabling biomarker-guided patient selection.