Unbiased Lipidomic Profiling of Triple-Negative Breast Cancer Tissues Reveals the Association of Sphingomyelin Levels with Patient Disease-Free Survival

Abstract

The reprogramming of lipid metabolism is a hallmark of many cancers that has been shown to promote breast cancer progression. While several lipid signatures associated with breast cancer aggressiveness have been identified, a comprehensive lipidomic analysis specifically targeting the triple-negative subtype of breast cancer (TNBC) may be required to identify novel biomarkers and therapeutic targets for this most aggressive subtype of breast cancer that still lacks effective therapies. In this current study, our global LC-MS-based lipidomics platform was able to measure 684 named lipids across 15 lipid classes in 70 TNBC tumors. Multivariate survival analysis found that higher levels of sphingomyelins were significantly associated with better disease-free survival in TNBC patients. Furthermore, analysis of publicly available gene expression datasets identified that decreased production of ceramides and increased accumulation of sphingoid base intermediates by metabolic enzymes were associated with better survival outcomes in TNBC patients. Our LC-MS lipidomics profiling of TNBC tumors has, for the first time, identified sphingomyelins as a potential prognostic marker and implicated enzymes involved in sphingolipid metabolism as candidate therapeutic targets that warrant further investigation.

Effect of Estrogen Receptor Status on Circulatory Immune and Metabolomics Profiles of HER2-Positive Breast Cancer Patients Enrolled for Neoadjuvant Targeted Chemotherapy

“…The reprogramming of the lipid metabolism represents one of the hallmarks of many cancers, including BC, being able to promote and sustain cancer progression [38]. Moreover, the ER status itself has been found to dramatically influence the lipid profiles, with the highest levels of membrane phospholipids detected in the most aggressive tumors [39,40]. The stimulating effect of lipids on BC tumor growth seems also be sustained by the observation that high levels of LDL-cholesterol at the time of diagnosis may have a negative prognostic value [41].…”

Large‐scale profiling of serum metabolites in African American and European American patients with bladder cancer reveals metabolic pathways associated with patient survival

“…Metabolic extraction was performed as described previously. 12,13,[24][25][26] Briefly, serum samples were stored at -80°C until the analysis. Serum (40 µL) was used for metabolite extraction; the serum pool was used as a quality control.…”

Understanding the Lipidome at the Systems Level with lipidomeR

“…Next, we analyzed lipidomic differences between tissue from breast cancer and benign breast tumor, allowing us to test also lipidomeR's statistical inference functionality and the integration of statistics results over the visualization of the lipidome. In this study 13 Figure 3). On the other hand, DGs are mainly reduced in cancer but, specifically, 38-carbon DGs break this rule with a consistent elevation (see the DG panel of Figure 3 at y = 38).…”

“…We thank the authors of the human lipidome study 12 , the authors and donors of the breast cancer study 13 and the authors and donors of the NAFLD study 14 for providing their data with an open access. We thank the Metabolomics Workbench 20 for providing a platform for open-access metabolomics data, where also these lipidomics data sets had been deposited.…”