ACSS2-mediated metabolic-epigenetic crosstalk drives Fulvestrant resistance and represents a novel therapeutic target
5 affiliations
- 1Division of Nutritional Sciences, University of Illinois, Urbana-Champaign
- 2Department of Food Science and Human Nutrition, University of Illinois, Urbana-Champaign
- 3Carle Illinois College of Medicine, University of Illinois Urbana-Champaign
- 4Department of Molecular and Integrative Physiology, University of Illinois, Urbana-Champaign
- 5Carle Foundation Hospital
Abstract
Endocrine therapies targeting estrogen receptor alpha (ERα), expressed in ~70% of breast cancers, remain the standard of care for ER+ disease. However, 30–40% of patients experience recurrence and metastasis, with 5-year survival rates of only 31.9%. Using the Carle Foundation Hospital cohort and liver metastatic patient-derived xenograft models, we identified upregulated lipid metabolism and acetyl-CoA production as metabolic vulnerabilities. We demonstrate that combining Fulvestrant (Fulv) with an inhibitor of Acyl-CoA Synthetase Short Chain Family Member 2 (ACSS2) synergistically reduces metastatic breast cancer cell viability. Through isotope tracing, CUT&RUN sequencing, immunofluorescence, western blot, and RNA sequencing, we show that Fulv increases ACSS2 expression and acetate utilization, redirecting acetate flux from the TCA cycle toward fatty acid synthesis. Nuclear ACSS2 chromatin occupancy increases with Fulv treatment, expanding ERα/ACSS2/H3K27ac co-occupancy at tumor progression genes, an effect abolished by ACSS2 inhibition. RNA sequencing revealed that ACSS2 inhibition suppresses Fulv-induced metabolic and oncogenic transcriptional programs. In a therapy-resistant xenograft model, combination treatment reduced Fulv-dependent metastatic burden. These findings establish ACSS2 as a driver of endocrine resistance through nuclear acetyl-CoA provision for epigenetic reprogramming, representing a novel therapeutic target in metastatic breast cancer.
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BibTeX
@article{mogol2026acss2mediated,
title = {{ACSS2-mediated metabolic-epigenetic crosstalk drives Fulvestrant resistance and represents a novel therapeutic target}},
author = {Ayça N. Mogol and Jin Young Yoo and Alicia Arredondo Eve and Mahima Goel and David J. Dutton and Claire P. Schane and Audrey Lam and Debapriya Dutta and Betsy Barnick and Eda D. Erdogan and Erik R. Nelson and Maria Grosse-Perdekamp and Zeynep Madak-Erdogan},
journal = {npj Breast Cancer},
year = {2026},
month = jun,
doi = {10.1038/s41523-026-00987-0},
url = {https://doi.org/10.1038/s41523-026-00987-0},
note = {CC BY},
}
RIS
TY - JOUR
TI - ACSS2-mediated metabolic-epigenetic crosstalk drives Fulvestrant resistance and represents a novel therapeutic target
AU - Ayça N. Mogol
AU - Jin Young Yoo
AU - Alicia Arredondo Eve
AU - Mahima Goel
AU - David J. Dutton
AU - Claire P. Schane
AU - Audrey Lam
AU - Debapriya Dutta
AU - Betsy Barnick
AU - Eda D. Erdogan
AU - Erik R. Nelson
AU - Maria Grosse-Perdekamp
AU - Zeynep Madak-Erdogan
PY - 2026
DA - 2026/06/01
JO - npj Breast Cancer
DO - 10.1038/s41523-026-00987-0
UR - https://doi.org/10.1038/s41523-026-00987-0
AB - Endocrine therapies targeting estrogen receptor alpha (ERα), expressed in ~70% of breast cancers, remain the standard of care for ER+ disease. However, 30–40% of patients experience recurrence and metastasis, with 5-year survival rates of only 31.9%. Using the Carle Foundation Hospital cohort and liver metastatic patient-derived xenograft models, we identified upregulated lipid metabolism and acetyl-CoA production as metabolic vulnerabilities. We demonstrate that combining Fulvestrant (Fulv) with an inhibitor of Acyl-CoA Synthetase Short Chain Family Member 2 (ACSS2) synergistically reduces metastatic breast cancer cell viability. Through isotope tracing, CUT&RUN sequencing, immunofluorescence, western blot, and RNA sequencing, we show that Fulv increases ACSS2 expression and acetate utilization, redirecting acetate flux from the TCA cycle toward fatty acid synthesis. Nuclear ACSS2 chromatin occupancy increases with Fulv treatment, expanding ERα/ACSS2/H3K27ac co-occupancy at tumor progression genes, an effect abolished by ACSS2 inhibition. RNA sequencing revealed that ACSS2 inhibition suppresses Fulv-induced metabolic and oncogenic transcriptional programs. In a therapy-resistant xenograft model, combination treatment reduced Fulv-dependent metastatic burden. These findings establish ACSS2 as a driver of endocrine resistance through nuclear acetyl-CoA provision for epigenetic reprogramming, representing a novel therapeutic target in metastatic breast cancer.
SN - 2374-4677
ER -