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Lipid metabolic reprogramming drives triglyceride storage and variable sensitivity to FASN inhibition in

Ashley V Ward1, Duncan Riley1, Kirsten E Cosper1

  • 1Department of Pathology, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA.

Breast Cancer Research : BCR
|March 7, 2025
PubMed
Abstract

Insights

Endocrine-resistant breast cancer cells alter lipid metabolism, increasing triglycerides and polyunsaturated fatty acids (PUFAs). A fatty acid synthase inhibitor reduced lipid storage but not cell growth, suggesting PUFA pathway targeting for new therapies.

Area of Science:

  • Oncology
  • Metabolic Research
  • Biochemistry

Background:

  • Lipid metabolic reprogramming is a key feature of endocrine resistance in estrogen receptor-positive (ER+) breast cancer.
  • Investigating these metabolic alterations is crucial for understanding and overcoming treatment resistance.

Purpose of the Study:

  • To investigate lipid metabolism alterations in ER+ breast cancer cells resistant to endocrine therapies.
  • To evaluate the efficacy of a fatty acid synthase (FASN) inhibitor in these resistant cells.

Main Methods:

  • Derived endocrine-resistant ER+ breast cancer cell lines (Tamoxifen-resistant, Fulvestrant-resistant, estrogen-deprived).
  • Performed gene expression and lipidomic profiling, Oil Red O staining for lipid droplets.
  • Assessed FASN activity and inhibitor (TVB-2640) efficacy using 13C2-acetate tracing.

Main Results:

  • Resistant cells showed enriched lipid metabolism, elevated triglycerides, and increased lipid droplets.
  • FASN activity was higher in resistant cells; TVB-2640 reduced FASN activity and lipid storage in most cell lines.
  • Polyunsaturated fatty acids (PUFAs) with high desaturation increased in resistant cells, unaffected or increased by TVB-2640; cell growth inhibition was limited.

Conclusions:

  • Endocrine-resistant breast cancer exhibits a metabolic shift towards triglyceride and highly desaturated PUFA accumulation.
  • Fatty acid synthase inhibition shows limited efficacy on cell growth, despite reducing lipid storage.
  • Targeting specific lipid metabolic pathways, especially those producing PUFAs, may offer a therapeutic strategy for endocrine-resistant breast cancer.
Keywords:
Breast cancerEndocrine resistance, lipid metabolismFatty acidFatty acid synthaseLipidomics

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