Abstract
Sphingosine‐1‐phosphate (S1P) is a bioactive lipid that exerts various pathophysiological functions through binding to its receptor family (S1PRs). Since first report of the breast cancer (BCA) promoting function by S1P production (through the function of sphingosine kinases) and S1P/S1PR signaling, their antagonists have never been successfully progress to clinics after three decades. Taking advantage of bioinformatics linking to gene expression to disease prognosis, we examined the impact of associated genes in BCA patients. We found high gene expressions involved in S1P anabolism suppressed disease progression of patients who are basal cell type BCA or receiving adjuvant therapy. In addition, S1PRs expression also suppressed disease progress of multiple categories of BCA patient progression. This result is contradictory to tumor promoter role of S1P/S1PRs which revealed in the literature. Further examination by directly adding S1P in BCA cells found a cell growth suppression function, which act via the expression of S1PR1. In conclusion, our study is the first evidence claiming a survival benefit function of S1P/S1PR signaling in BCA patients, which might explain the obstacle of relative antagonist apply in clinics.
Highlights
Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid metabolite involved in many pathophysiological processes.[1,2,3,4] The intracellular level of S1P as a secondary messenger 5 is regulated by several enzymes including anabolism and catabolism
Such as sphingosine kinases 1 and 2 (SPHK1, SPHK2) that are responsible for S1P synthesis
The function of S1P is go through its receptors S1P receptors (S1PRs) (S1PR1-5) which belongs to the G-p rotein coupled receptor (GPCR) family 2 and each receptor, respectively, involved in cell growth, apoptosis, proliferation, angiogenesis, chemo resistance, or vascular stability.[5,13,14,15]
Summary
Taiwan Ministry of Science and Technology, Grant/Award Number: MOST104-2314-B-039-046, 106-2320-B039-008 and 106-2221-E-039-011-MY3; Taiwan National Health Research Institute, Grant/Award Number: NHRI-EX10710705BI; Taiwan Ministry of Health and Welfare Clinical Trial; Research Center of Excellence, Grant/Award Number: MOHW106-TDU-B-212-133019 and MOHW106-TDU-B-212-113006; China Medical University/Hospital, Grant/Award Number: CMU106-S-30, CMU106-N-05 and DMR-107-075; Chia-Yi Chang-Gong Memorial Hospital, Grant/Award Number: CMRPG6G0111, CMRPG8D0743 and CMRPG6E0122
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