Journal Article

Lipid metabolic reprogramming drives triglyceride storage and variable sensitivity to FASN inhibition in endocrine-resistant breast cancer cells

Kabos, Peter, Finlay-Schultz, Jessica, Hill, Kaitlyn B., Varshney, Rohan R., Libby, Andrew E., Sartorius, Carol A., Ward, Ashley V., Rudolph, Michael C., Cosper, Kirsten E., Brechbuhl, Heather M., Riley, Duncan

2025

Overview

Background Lipid metabolic reprogramming is increasingly recognized as a hallmark of endocrine resistance in estrogen receptor-positive (ER+) breast cancer. In this study, we investigated alterations in lipid metabolism in ER + breast cancer cell lines with acquired resistance to common endocrine therapies and evaluated the efficacy of a clinically relevant fatty acid synthase (FASN) inhibitor. Methods ER + breast cancer cell lines resistant to Tamoxifen (TamR), Fulvestrant (FulvR), and long-term estrogen withdrawal (EWD) were derived. Global gene expression and lipidomic profiling were performed to compare parental and endocrine resistant cells. Lipid storage was assessed using Oil Red O (ORO) staining. The FASN inhibitor TVB-2640 was tested for its impact on lipid storage and cell growth. 13 C 2 -acetate tracing was used to evaluate FASN activity and the efficacy of TVB-2640. Results Endocrine resistant cells showed significant enrichment in lipid metabolism pathways and distinct lipidomic profiles, characterized by elevated triglyceride levels and enhanced cytoplasmic lipid droplets. 13 C 2 -acetate tracing revealed increased FASN activity in endocrine resistant cells, which was effectively reduced by TVB-2640. While TVB-2640 reduced lipid storage in most but not all cell lines, this did not correlate with decreased cell growth. Polyunsaturated fatty acids (PUFAs) containing 6 or more double bonds were elevated in endocrine resistant cells and remained unaffected or increased with TVB-2640. Conclusion Endocrine resistant breast cancer cells undergo a metabolic shift toward increased triglyceride storage and PUFAs with high degrees of desaturation. While TVB-2640 reduced lipid storage in most conditions, it had limited effects on the growth of endocrine resistant breast cancer cells. Targeting specific lipid metabolic dependencies, particularly pathways that produce PUFAs, represents a potential therapeutic strategy in endocrine resistant breast cancer.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Acetates / Acetic acid / Amino acids / Antineoplastic Agents, Hormonal - pharmacology / Biomedical and Life Sciences / Biomedicine / Biosynthesis / Breast cancer / Breast Neoplasms - drug therapy / Breast Neoplasms - genetics / Breast Neoplasms - metabolism / Breast Neoplasms - pathology / Cancer / Cancer cells / Cancer Research / Cancer therapies / Cell growth / Cell Line, Tumor / Cell Proliferation - drug effects / Chemical properties / Cholesterol / Drug dosages / Drug Resistance, Neoplasm - drug effects / Endocrine resistance, lipid metabolism / Endocrine therapy / Enzymes / Estrogen / Estrogen receptors / Estrogens / Fatty acid / Fatty acid synthase / Fatty Acid Synthase, Type I - antagonists & inhibitors / Fatty Acid Synthase, Type I - metabolism / Fatty acids / Female / Fulvestrant / Fulvestrant - pharmacology / Gene expression / Gene Expression Regulation, Neoplastic - drug effects / Humans / Kinases / Lipid metabolism / Lipid Metabolism - drug effects / Lipidomics / Lipids / Metabolic Reprogramming / Metabolism / Mutation / Oncology / Polyunsaturated fatty acids / Receptors, Estrogen - metabolism / Surgical Oncology / Synthesis / Tamoxifen - pharmacology / Triglycerides / Triglycerides - metabolism / Tumor cell lines / Tumors / Unsaturated fatty acids