Abstract P1-01-21: The levels of sphingosine-1-phosphate and its related gene expressions in breast cancer patients
Authors: Tsuchida J , Nagahashi M , Nakajima M , Takabe K , Wakai T 
Published: February 2018

Background: The bioactive lipid mediator sphingosine-1-phosphate (S1P) has emerged as a key regulatory molecule in cancer progression. We previously demonstrated that S1P is a crucial mediator of breast cancer-induced angiogenesis and lymphangiogenesis, and promote metastasis. Although increasing number of in vitro and in vivo experiments have revealed the importance of S1P in cancer progression, the data on the roles of S1P in human patients are very limited. The aim of this study is to reveal the clinical relevance of S1P in the interaction between cancer and the tumor microenvironment by examining the levels of the sphingolipids in patient breast cancer tissue samples.

Material and Method: Breast cancer tissue, peri-tumor tissue, and normal breast tissue were collected from 20 breast cancer patients immediately after surgery that were conducted from November 2015 to February 2016 at Niigata University Medical and Dental Hospital. Sphingolipids were quantified by liquid chromatography–electrospray ionization tandem mass spectrometry. The expression level of each enzyme-encoding gene involved in S1P production was evaluated by retrieving RNA sequencing and gene expression quantification data from breast cancer tissues (n = 112) and paired normal breast tissues (n = 112) using the Genomics Data Commons (GDC) data portal of the The Cancer Genome Atlas (TCGA) cohort. Gene expression levels were derived using normalization methods provided in the DESeq2 package.

Result: The levels of the sphingolipids sphingosine (Sph), dihydro-sphingosine (DHSph), S1P, and dihydro-S1P (DHS1P) were successfully determined in breast cancer, peri-tumor, and normal breast tissues from all of the 20 patients. As expected, a one-way ANOVA revealed that S1P levels were significantly different depending on the location (F(2,57) = 7.029, P = 0.002). The Tukey post hoc test revealed that S1P levels in tumors were significantly higher than those in normal breast tissue and peri-tumor tissue (P &lt; 0.05). Similarly, Sph and DHSph levels in tumors were significantly higher than in normal breast tissue and peri-tumor tissue. Both SPHK1 and SPHK2 gene expression levels in breast cancer tissue were higher than those in normal breast tissue. Interestingly, expression of some of the S1P-related genes; S1PR3, ABCC1, SGPL1, and ORMDL2, were significantly increased in the breast cancer tissue compared to normal breast tissue. On the other hand, there was significantly decreased expression of the S1P-related genes S1PR1, S1PR2, ABCG2, SPNS2, SGPP1 and ORMDL3, in breast cancer tissue compared to normal breast tissue.

Conclusion: We demonstrated that the major source of S1P is the tumor tissue, and not the peri-tumor tissue despite the fact that angiogenesis and lymphangiogenesis are occurring more in the peri-tumor area, which implicate that S1P may have further role inside the tumor. Our results indicated the complexity of S1P signaling in human cancer than expected based on the results in vivo experiments.

Citation Format: Tsuchida J, Nagahashi M, Nakajima M, Takabe K, Wakai T. The levels of sphingosine-1-phosphate and its related gene expressions in breast cancer patients [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-01-21.