Abstract

Sphingolipids have emerged as key regulatory molecules in cancer cell survival and death. Although important roles of sphingolipids in breast cancer progression have been reported in experimental models, their roles in human patients are yet to be revealed. The aim of this study was to investigate the ceramide levels and its biosynthesis pathways in human breast cancer patients. Breast cancer, peri-tumor and normal breast tissue samples were collected from surgical specimens from a series of 44 patients with breast cancer. The amount of sphingolipid metabolites in the tissue were determined by mass spectrometry. The Cancer Genome Atlas was used to analyze gene expression related to the sphingolipid metabolism. Ceramide levels were higher in breast cancer tissue compared to both normal and peri-tumor breast tissue. Substrates and enzymes that generate ceramide were significantly increased in all three ceramide biosynthesis pathways in cancer. Further, higher levels of ceramide in breast cancer were associated with less aggressive cancer biology presented by Ki-67 index and nuclear grade of the cancer. Interestingly, patients with higher gene expressions of enzymes in the three major ceramide synthesis pathways showed significantly worse prognosis. This is the first study to reveal the clinical relevance of ceramide metabolism in breast cancer patients. We demonstrated that ceramide levels in breast cancer tissue were significantly higher than those in normal tissue, with activation of the three ceramide biosynthesis pathways. We also identified that ceramide levels have a significant association with aggressive phenotype and its enzymes have prognostic impact on breast cancer patients.

Highlights

  • Breast cancer is the leading cause of cancer-related deaths among women worldwide, and the estimated number of deaths is over 40,000 among women in the US in 2018 [1]

  • We demonstrated that ceramide levels in breast cancer tissue were significantly higher than those in normal breast tissue, with activation of the three ceramide biosynthesis pathways

  • We found that sphingomyelin phosphodiesterase 2 (SMPD2), sphingomyelin phosphodiesterase 4 (SMPD4), and sphingomyelin phosphodiesterase 5 (SMPD5) were significantly higher in breast cancer tissue than that in paired normal breast tissue, while sphingomyelin synthase 2 (SGMS2) was significantly decreased in breast cancer tissue (TCGA cohort, n=112) (Figure 4C)

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Summary

Introduction

Breast cancer is the leading cause of cancer-related deaths among women worldwide, and the estimated number of deaths is over 40,000 among women in the US in 2018 [1]. We have demonstrated that S1P levels are high in tumors [4], and in the tumor microenvironment [12]. We further demonstrated that high S1P production by tumor is associated with lymph node metastasis [13], indicating that S1P promotes cancer metastasis by affecting tumor microenvironment in human breast cancer. It was of interest to analyze the ceramide levels of cancer, peri-tumor, normal breast tissue and interstitial fluid (that is a component of tumor microenvironment), since ceramide has not been as extensively studied and may have important relationships with cancer

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