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

// Kazuki Moro 1 , Tsutomu Kawaguchi 2 , Junko Tsuchida 1 , Emmanuel Gabriel 2 , Qianya Qi 3 , Li Yan 3 , Toshifumi Wakai 1 , Kazuaki Takabe 1, 2, 4, 5, 6 and Masayuki Nagahashi 1 1 Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata City 951-8510, Japan 2 Breast Surgery, Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, New York 14263, USA 3 Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, New York 14263, USA 4 Department of Surgery, University at Buffalo Jacobs School of Medicine and Biomedical Sciences, The State University of New York, Buffalo, New York 14203, USA 5 Department of Breast Surgery and Oncology, Tokyo Medical University, Tokyo 160-8402, Japan 6 Department of Surgery, Yokohama City University, Yokohama 236-0004, Japan Correspondence to: Masayuki Nagahashi, email: mnagahashi@med.niigata-u.ac.jp Kazuaki Takabe, email: kazuaki.takabe@roswellpark.org Keywords: breast cancer; ceramide; metabolism; prognosis; sphingolipid Received: October 07, 2017     Accepted: March 12, 2018     Published: April 13, 2018 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.