A study on the role of sphingolipid metabolism in drug resistance and metastasis in breast cancer patients

Abstract

Dysregulation in metabolic pathways to meet the bioenergetic and biosynthetic requirements has become a principal characteristic of cancer cells. Lipid moieties are not only a concentrated source of energy but also provide many precursors to fuel the rapid proliferation rate in cancer and thus are of physiological and clinical relevance. Sphingolipids (SPLs) are the largest class of lipids with both structural and signaling properties and have been associated to various aspects of tumorigenesis. Though sphingolipid metabolism has been extensively studied in cancer cell lines and experimental models, the clinical relevance of their metabolites in human malignancies is still poorly understood and needs further investigation. In the present study, we adopted a UHPLC-High resolution (orbitrap) Mass spectrometry (HRMS) approach to identify dysregulations in the levels of sphingolipid metabolites in breast cancer patient samples. The present study reports an elevation in the levels of ceramide phosphate (CerP) and sphingosine phosphates (S1P) in tumor tissues as compared to adjacent normal tissues. The clinical correlations of the above metabolites and their performance as biomarkers was also evaluated. The above findings were validated by analyzing the expression of CERK and SPHK1 genes in the local as well as TCGA cohort and their clinical relevance in breast cancer was also determined. Furthermore, the association of CERK and SPHK1 with metastasis markers MMP-2 and MMP-9 and drug resistance marker genes ABCC1 and ABCG2 reinforce the significance of these sphingolipids as diagnostic and prognostic biomarkers in breast cancer patients. newline