Survival benefit of sphingosin‐1‐phosphate and receptors expressions in breast cancer patients

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.

Does the Sphingosine 1-Phosphate Receptor-1 Provide a Better or Worse Prognostic Outcome for Breast Cancer Patients?

“…In contrast, the S1P 2 receptor has been linked with inhibition of cell migration ( 17 ). Therefore, the findings by Lei et al ( 8 ) regarding the effect of shRNA knockdown of S1P 2 are in fact consistent with a relief of the inhibitory constraint of S1P 2 on the migration of MCF-7 and MDA-MB-231 cells in response to added S1P. This would reduce colony formation by enhancing dispersal and thereby preventing colony residency.…”

“…Therefore, a reciprocal relationship could exist between mRNA and protein levels. In this case, interpretation of the results by Lei et al ( 8 ) would be completely reversed. For instance, it could be concluded that high expression of S1P 1 protein (low mRNA transcript) in BCA tumors is linked with a poorer prognosis.…”

“…High SphK1 mRNA in tumors had no effect on 10 year relapse free disease survival, while high SphK2 mRNA was found to have a positive impact in patients with non-classified, or basal type BCA and those who had received adjuvant therapy. Lei et al ( 8 ) also reported that high S1P 1 mRNA in tumors was associated with improved survival in patients with non-classified BCA and in those receiving treatment, but had no effect on patients with basal cell type BCA. In addition, improved survival was associated with high S1P 2 mRNA in tumors from patients with non-classified BCA, basal cell type BCA and those patients receiving treatment.…”

“…Lei et al ( 8 ) used data mining and the Kaplan-Meier plotter ( http://kmplot.com/analysis/index.php?p=service&cancer=breast ) to establish relationships between messenger RNA levels (rather than protein) of SphK1, SphK2, sphingosine 1-phosphate receptor 1 (S1P 1 ), or sphingosine 1-phosphate receptor 2 (S1P 2 ) and 10 year relapse free survival of non-classified breast cancer (BCA) patients. High SphK1 mRNA in tumors had no effect on 10 year relapse free disease survival, while high SphK2 mRNA was found to have a positive impact in patients with non-classified, or basal type BCA and those who had received adjuvant therapy.…”

“…To provide a mechanistic explanation for the clinical findings, Lei et al ( 8 ) reported the inhibition of colony formation by MCF-7 cells (ER + ) or triple negative MDA-MB-231 cells in response to treatment with S1P (4–10 μM) for 2 weeks. Using shRNA knockdown of either S1P 1 or S1P 2 in MCF-7 and MDA-MB-231 cells, the authors showed that the inhibitory effect of S1P on colony formation was enhanced in both cell types upon S1P 2 knockdown whereas S1P 1 knockdown reduced the effect in MDA-MB-231 cells and was without effect in MCF-7 cells.…”