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Published on: June 17, 2022

ACSS2-mediated metabolic-epigenetic crosstalk drives Fulvestrant resistance and represents a novel therapeutic target

Ayça N Mogol1,2,3, Jin Young Yoo3, Alicia Arredondo Eve3

  • 1Division of Nutritional Sciences, University of Illinois, Urbana-Champaign, Urbana, IL, USA.

NPJ Breast Cancer
|June 27, 2026
PubMed

Insights

Combining Fulvestrant with an ACSS2 inhibitor synergistically reduces metastatic breast cancer cell viability. This combination targets endocrine resistance by blocking epigenetic reprogramming driven by nuclear acetyl-CoA, offering a new therapeutic strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Metabolic Research

Background:

  • Estrogen receptor alpha (ERα)-positive breast cancer is common, but endocrine therapies often fail, leading to recurrence and metastasis.
  • Metastatic breast cancer has poor survival rates, highlighting the need for novel therapeutic targets.
  • Upregulated lipid metabolism and acetyl-CoA production are identified as key metabolic vulnerabilities in metastatic breast cancer.

Purpose of the Study:

  • To investigate the role of Acyl-CoA Synthetase Short Chain Family Member 2 (ACSS2) in endocrine resistance in metastatic breast cancer.
  • To evaluate the synergistic effect of combining Fulvestrant (Fulv) with an ACSS2 inhibitor on metastatic breast cancer cell viability.
  • To elucidate the mechanism by which ACSS2 contributes to endocrine resistance and epigenetic reprogramming.

Main Methods:

  • Utilized patient-derived xenograft models and a clinical cohort (Carle Foundation Hospital).
  • Employed isotope tracing, CUT&RUN sequencing, immunofluorescence, western blot, and RNA sequencing.
  • Assessed the impact of Fulv and ACSS2 inhibition on cell viability, gene expression, and epigenetic modifications.

Main Results:

  • Combining Fulvestrant with an ACSS2 inhibitor synergistically reduced metastatic breast cancer cell viability.
  • Fulvestrant treatment increased ACSS2 expression and acetate utilization, redirecting metabolic flux towards fatty acid synthesis.
  • ACSS2 inhibition abolished Fulv-induced epigenetic changes and suppressed oncogenic transcriptional programs, reducing metastatic burden in resistant models.

Conclusions:

  • ACSS2 drives endocrine resistance in metastatic breast cancer by providing nuclear acetyl-CoA for epigenetic reprogramming.
  • Targeting ACSS2 in combination with Fulvestrant represents a promising therapeutic strategy for overcoming endocrine resistance.
  • ACSS2 is identified as a novel therapeutic target for metastatic breast cancer.

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