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. 2016 Aug;204(2):435-444.
doi: 10.1016/j.jss.2016.05.022. Epub 2016 May 20.

High levels of sphingolipids in human breast cancer

Masayuki Nagahashi  1 , Junko Tsuchida  2 , Kazuki Moro  2 , Miki Hasegawa  2 , Kumiko Tatsuda  2 , Ingrid A Woelfel  3 , Kazuaki Takabe  3 , Toshifumi Wakai  2
Affiliations

High levels of sphingolipids in human breast cancer

Masayuki Nagahashi et al. J Surg Res. 2016 Aug.

Abstract

Background: Sphingolipids, including sphingosine-1-phosphate (S1P) and ceramide, have emerged as key regulatory molecules that control various aspects of cell growth and proliferation in cancer. Although important roles of sphingolipids in breast cancer progression have been reported in experimental models, their roles in human patients have yet to be determined. The aims of this study were to determine the levels of sphingolipids including S1P, ceramides, and other sphingolipids, in breast cancer and normal breast tissue and to compare the difference in levels of each sphingolipid between the two tissues.

Materials and methods: Tumor and noncancerous breast tissue were obtained from 12 patients with breast cancer. Sphingolipids including S1P, ceramides, and their metabolites of sphingosine, sphingomyelin, and monohexosylceramide were measured by liquid chromatography-electrospray ionization-tandem mass spectrometry.

Results: The levels of S1P, ceramides, and other sphingolipids in the tumor were significantly higher than those in normal breast tissue. There was a relatively strong correlation in the levels of S1P between the tumor and those of normal breast tissue from the same person. On the other hand, there was no correlation in the levels of most of the ceramide species between the tumor and those of normal breast tissue from the same person.

Conclusions: To our knowledge, this is the first study to reveal that levels of sphingolipids in cancer tissue are generally higher than those of normal breast tissue in patients with breast cancer. The correlation of S1P levels in these tissues implicates the role of S1P in interaction between cancer and the tumor microenvironment.

Keywords: Breast cancer; Ceramides; Sphingosine-1-phosphate; Tumor microenvironment.

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Conflict of interest statement

There are no potential conflicts of interest to disclose. This work was supported by the Japan Society for the Promotion of Science (JSPS) Grant-in-Aid for Scientific Research Grant Number 15H05676 and 15K15471 for M.N., 16K19888 for J.T., and 15H04927 for T.W. M.N. is supported by the Uehara Memorial Foundation, Nakayama Cancer Research Institute, Takeda Science Foundation, and Tsukada Medical Foundation. K.T. is supported by NIH/NCI grant R01CA160688 and Susan G. Komen Investigator Initiated Research Grant IIR12222224.

Figures

Fig. 1
Fig. 1
Levels of sphingosine-1-phosphate (S1P) and other sphingolipids in breast cancer and normal breast tissue. The levels of the sphingolipids including sphingosine (Sph), dihydro-Sph (DHSph), S1P, dihydro-S1P (DHS1P) were determined by LC-ESI-MS/MS. Mean values are shown by horizontal lines.
Fig. 2
Fig. 2
Correlation between levels of sphingosine-1-phosphate (S1P) and other sphingolipids in breast cancer and those in normal breast tissue. The correlation between two variables are denoted by R2. R2 ≧ 0.81 is considered a large positive linear association and R2 ≧ 0.20 is considered a small positive linear association.
Fig. 3
Fig. 3
Levels of sphingomyelin (SM) in breast cancer and normal breast tissue. The levels of sphingomyelin (C14:0, C16:0, C18:1, C18:0, C20:0, C22:0, C24:1, C24:0, C26:1, C26:0) were determined by LC-ESI-MS/MS. Mean values are shown by horizontal lines.
Fig. 4
Fig. 4
Correlation between levels of sphingomyelin in breast cancer and those in normal breast tissue. The correlation between two variables are denoted by R2. R2 ≧ 0.81 is considered a large positive linear association and R2 ≧ 0.20 is considered a small positive linear association.
Fig. 5
Fig. 5
Levels of monohexosylceramides (HexCer) in breast cancer and normal breast tissue. The levels of HexCer (C14:0, C16:0, C18:1, C18:0, C20:0, C22:0, C24:1, C24:0, C26:1, C26:0) were determined by LC-ESI-MS/MS. Mean values are shown by horizontal lines.
Fig. 6
Fig. 6
Correlation between levels of monohexosylceramides in breast cancer and those in normal breast tissue. The correlation between two variables are denoted by R2. R2 ≧ 0.81 is considered a large positive linear association and R2 ≧ 0.20 is considered a small positive linear association.
Fig. 7
Fig. 7
Levels of Ceramides in breast cancer and normal breast tissue. The levels of Ceramides (C14:0, C16:0, C18:1, C18:0, C20:0, C22:0, C24:1, C24:0, C26:1, C26:0) were determined by LC-ESI-MS/MS. Mean values are shown by horizontal lines.
Fig. 8
Fig. 8
Correlation between levels of ceramides in breast cancer and those in normal breast tissue. The correlation between two variables are denoted by R2. R2 ≧ 0.81 is considered a large positive linear association, and R2 ≧ 0.20 is considered a small positive linear association.
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