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

Preeti Purwaha,Theckelnaycke Rajendiran,Arun Sreekumar,Sao Jiralerspong,Danthasinghe Piyarathna,Angela Omilian,Christine Ambrosone,Anindita Ravindran,Franklin Gu,Nagireddy Putluri,Cristian Coarfa,Gokul Das,Carl Morrison

doi:10.3390/metabo8030041

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.

Highlights

Triple-negative breast cancer (TNBC) comprises a heterogeneous subgroup of breast tumors characterized by an aggressive clinical course and increased likelihood of recurrence [1,2]
Several studies have shown that lipids can serve as biomarkers to differentiate breast tumor from normal tissues and that changes in lipid levels are associated with disease progression and hormone receptor status in breast tumors [30]
Our platform was able to identify an increase in phospholipids and a reduction in glycerolipids in AA compared to EA triple-negative subtype of breast cancer (TNBC) tumors

Summary

Introduction

Triple-negative breast cancer (TNBC) comprises a heterogeneous subgroup of breast tumors characterized by an aggressive clinical course and increased likelihood of recurrence [1,2]. Sphingolipids are a class of membrane lipids implicated in breast cancer progression [12,13,14]. In addition to their role in maintaining membrane structure, sphingolipids such as ceramide and sphingosine-1-phosphate (S1P) serve as messengers in lipid signaling in cancer cells [15,16,17,18,19,20,21]. S1P production by cancer cells simulates angiogenesis through lipid signaling to the tumor microenvironment [24,25]. It has been shown that sphingoid bases such as sphinganine and sphingosine, which serve as metabolic intermediates in the synthesis of ceramide and

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