Ceramide species are elevated in human breast cancer and are associated with less aggressiveness

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.

Golgi-localized PAQR4 mediates Anti-apoptotic Ceramidase Activity in Breast Cancer

“…Beyond their structural role in the membrane homeostasis, sphingolipids control critical signaling transduction pathways within the cancer cells to drive growth, proliferation, migration and invasion. Altered levels of ceramide species and other metabolites in the sphingolipid metabolism network of the cancer cells is related to the deregulation of the expression of the genes encoding the enzymes within this network (Moro et al, 2018).…”

“…Sphingolipids are key regulatory bioactive molecules that play important roles in cancer biology (Ogretmen, 2018). Altered sphingolipid metabolism are linked to several cancer types including liver, colon (Selzner et al, 2001), endometrial (Knapp et al, 2010) and breast cancer (Moro et al, 2018;Nagahashi et al, 2016). The levels of sphingolipid pathway metabolites, including ceramides and sphingosine-1-phosphate (S1P), are significantly deregulated in breast tumor tissue compared to normal tissue (Moro et al, 2018;Nagahashi et al, 2016), and elevated tumor ceramide levels have been shown to be associated with higher tumor grades (Moro et al, 2018;Schiffmann et al, 2009).…”

The role of sphingosine‐1‐phosphate in inflammation and cancer progression

“…63 Consequently, it is thought that the life or death of a cell is regulated by the balance between S1P and ceramide. 63 However, further research is needed to determine how the balance between S1P and ceramide is regulated to maintain cell homeostasis. Together, SphK, F I G U R E 2 Metabolism of sphingolipids.…”

“…S1P lyase is an enzyme that decomposes S1P irreversibly . S1P phosphatase is an enzyme that removes phosphate from S1P to produce sphingosine, which can then be converted to ceramide by ceramide synthase . Whereas S1P acts as a “cell survival signal” for cell proliferation and survival, ceramide acts as a “cell death signal” for cellular apoptosis .…”

“…S1P phosphatase is an enzyme that removes phosphate from S1P to produce sphingosine, which can then be converted to ceramide by ceramide synthase . Whereas S1P acts as a “cell survival signal” for cell proliferation and survival, ceramide acts as a “cell death signal” for cellular apoptosis . Consequently, it is thought that the life or death of a cell is regulated by the balance between S1P and ceramide .…”