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Lipid metabolic reprogramming drives triglyceride storage and variable sensitivity to FASN inhibition in
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.
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 pathways
- Breast cancer research
Background:
- Lipid metabolic reprogramming is a key feature of endocrine resistance in estrogen receptor-positive (ER+) breast cancer.
- Understanding these metabolic shifts is crucial for developing effective treatments for resistant breast cancer.
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 Tamoxifen (TamR), Fulvestrant (FulvR), and estrogen withdrawal (EWD) resistant ER+ breast cancer cell lines.
- Performed gene expression, lipidomic profiling, and Oil Red O staining.
- Assessed FASN activity and inhibitor efficacy using 13C2-acetate tracing and tested FASN inhibitor TVB-2640.
Main Results:
- Endocrine-resistant cells exhibited enriched lipid metabolism, elevated triglycerides, and increased lipid droplets.
- FASN activity was higher in resistant cells and reduced by TVB-2640, which decreased lipid storage in most cell lines.
- Polyunsaturated fatty acids (PUFAs) with high desaturation were elevated and unaffected by TVB-2640, which did not consistently inhibit cell growth.
Conclusions:
- Endocrine-resistant breast cancer cells shift metabolism towards triglyceride and PUFA storage.
- FASN inhibition has limited impact on resistant cell growth, highlighting the need for alternative strategies.
- Targeting specific PUFA synthesis pathways may offer a novel therapeutic approach for endocrine-resistant breast cancer.
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