K. Moro1, M. Nagahashi1, J. Tsuchida1, T. Niwano1, K. Tatsuda1, C. Toshikawa1, M. Hasegawa1, Y. Koyama1, T. Kobayashi1, S. Kosugi2, H. Kameyama1, H. Aoki3, K. Takabe3, T. Wakai1 1Niigata University Graduate School Of Medical And Dental Sciences,Digestive And General Surgery Niigata University,NIigata, NIIGATA, Japan 2Uonuma Kikan Hospital,Division Of Digestive And General Surgery,Minami-Uonuma, NIIGATA, Japan 3Virginia Commonwealth University School Of Medicine And The Massey Cancer Center,Surgical Oncology,Richmond, VA, USA
Introduction:
It is well established that obesity is associated with poor prognosis of breast cancer patients. Obesity evokes chronic inflammation, which stimulates cancer progression. Ceramide is a key metabolite in both anabolic and catabolic pathways of sphingolipids, and the very long fatty acyl chain (C24:0 and C22:0) ceramides are elevated both in the tissues and in the circulation of obesity, insulin resistance and diabetes. One of the mechanisms of obesity-mediated inflammation is due to release of ceramide from adipocytes after lipolysis. It has been reported that the ceramides and other obesity-related factors trigger activation of inflammasome that result in the secretion of inflammatory cytokines such as IL-1 beta, IL-6, and TNF-alpha under the obese condition. However, serum levels of ceramides in breast cancer patients associated with obesity have not been elucidated to date. In this study, we examine the levels of ceramides in breast cancer patients to reveal the association of the sphingolipids with obesity and breast cancer progression.
Methods:
A retrospective analysis was conducted of 59 patients with breast cancer, in whom the disease was diagnosed as stage I, II or III pathologically. The serum from the patients were obtained when the diagnosis was made and any treatment had been done before the blood collection. Ceramides (C14:0, C16:0, C18:1, C18:0, C20:0, C22:0, C24:1, C24:0, C26:0) were measured by liquid chromatography-electrospray ionization-tandem mass spectrometry . The levels of ceramides were analyzed with clinicopathological data of the patients.
Results:
Body mass index (BMI) was significantly associated with the pathological stage (P < 0.05). The levels of ceramides were detected successfully in the serum from 59 breast cancer patients. The levels of ceramide were not associated with clinical demographics of the patients including age, hormone receptors (ER, PgR) and HER2 status, Ki-67 index, nuclear grade, lymphatic and vascular invasion of the tumor. Interestingly, however, levels of C24:0 ceramide in patients with high BMI (> 25) was significantly higher than that in patients with normal BMI (< 22) (P < 0.05). Further, levels of C24:0 ceramide were significantly elevated with pathological stage (P < 0.05). C22:0 ceramide also showed trends of similar associations with BMI and pathological stage, albeit they were not statistically significant.
Conclusion:
Our results show an elevation of very long fatty acyl chain (C24:0 and C22:0) ceramides in serum of obesity-related breast cancer. Further studies are needed to elucidate the mechanism, and possible association with the prognosis. This work was supported by the Japan Society for the Promotion of Science Grant-in-Aid for Scientific Research Grant Number 15H05676 and 15K15471 for M.N and 15H04927 for W.T. M.N. is supported by the Uehara Memorial Foundation, Nakayama Cancer Research Institute, Takeda Science Foundation, and Tsukada Memorial Foundation.