Targeting Aromatase and HDACs in Hormone Receptor-Positive Breast Cancer: Molecular Interplay, Endocrine Resistance and Therapeutic Opportunities.
- 1Department of Pharmaceutical Biochemistry and Clinical Laboratory, Faculty of Pharmacy, "Iuliu-Hațieganu" University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania.
- 2Department of Inorganic Chemistry, Faculty of Pharmacy, "Iuliu-Hațieganu" University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania.
- 3Department of Medical Biochemistry, Faculty of Medicine, "Iuliu Hațieganu" University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania.
Abstract
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.
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BibTeX
@article{lucaciu2026targeting,
title = {{Targeting Aromatase and HDACs in Hormone Receptor-Positive Breast Cancer: Molecular Interplay, Endocrine Resistance and Therapeutic Opportunities.}},
author = {Roxana Liana Lucaciu and Adriana Corina Hangan and Luminița Simona Oprean and Lucia Maria Procopciuc},
journal = {International journal of molecular sciences},
year = {2026},
month = sep,
doi = {10.3390/ijms27198619},
url = {https://europepmc.org/article/MED/42883867},
note = {CC BY},
}
RIS
TY - JOUR
TI - Targeting Aromatase and HDACs in Hormone Receptor-Positive Breast Cancer: Molecular Interplay, Endocrine Resistance and Therapeutic Opportunities.
AU - Roxana Liana Lucaciu
AU - Adriana Corina Hangan
AU - Luminița Simona Oprean
AU - Lucia Maria Procopciuc
PY - 2026
DA - 2026/09/26
JO - International journal of molecular sciences
DO - 10.3390/ijms27198619
UR - https://europepmc.org/article/MED/42883867
AB - 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.
SN - 1422-0067
ER -