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Updated: Feb 12, 2026
A Pipeline to Investigate the Structures and Signaling Pathways of Sphingosine 1-Phosphate Receptors
Published on: June 8, 2022
Triple Negative Breast Cancer Depends on Sphingosine Kinase 1 (SphK1)/Sphingosine-1-Phosphate (S1P)/Sphingosine
Shushu Wang1, Yueyang Liang1, Wenxiao Chang2
1Breast Disease Center, Southwest Hospital, Third Military Medical University, Chongqing, China (mainland).
Abstract:
BACKGROUND Triple negative breast cancer (TNBC) has a more aggressive recurrence. Previous reports have demonstrated that sphingosine kinase 1 (SphK1) is a crucial regulator of breast cancer progression. However, the correlation of SphK1 with clinical prognosis has been poorly investigated. Thus, we aimed to elaborate the role of SphK1 in TNBC metastasis. MATERIAL AND METHODS We first determined the level of SphK1 in breast cancer tissue samples and breast cancer cells. Furthermore, the expression of HER2 and phosphor-SphK1 (pSphK1) in human breast cancer tissue samples was determined by immunohistochemical analysis. Associations between SphK1 and clinical parameters of tumors were analyzed. The activity of SphK1 was measured by fluorescence analysis. Extracellular sphingosine-1-phosphate (S1P) was detected using an ELISA kit. Associations between SphK1 and metastasis potential were analyzed by Transwell assay. RESULTS Levels of SphK1 in TNBC patients were significantly higher than levels in other patients with other breast tumors. The expression of SphK1 was positively correlated with poor overall survival (OS) and progression-free survival (PFS), as well as poor response to 5-FU and doxorubicin. The depression of SphK1 thus could repress the Notch signaling pathway, reduce migration, and invasion of TNBC cells in vivo and in vitro. Furthermore, silencing of SphK1 by Ad-SPHK1-siRNA or SphK1 inhibitor PF543 sensitized TNBCs to 5-FU and doxorubicin. Our results also indicated that SphK1 inhibition could effectively counteracts tumors metastasis via Notch signaling pathways, indicating a potentially anti-tumor strategy in TNBC. CONCLUSIONS We found that elevated levels of pSphK1 were positive correlation with high expression of S1P, which in turn promoted metastasis of TNBC through S1P/S1PR3/Notch signaling pathway.
Insights
Sphingosine kinase 1 (SphK1) is elevated in triple-negative breast cancer (TNBC), promoting metastasis via the S1P/S1PR3/Notch pathway. Inhibiting SphK1 may offer a new anti-tumor strategy for TNBC patients.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Triple-negative breast cancer (TNBC) exhibits aggressive recurrence patterns.
- Sphingosine kinase 1 (SphK1) is implicated in breast cancer progression, but its prognostic role in TNBC requires further investigation.
- Understanding SphK1's role in TNBC metastasis is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the role of Sphingosine kinase 1 (SphK1) in triple-negative breast cancer (TNBC) metastasis.
- To determine the correlation between SphK1 expression and clinical prognosis in TNBC patients.
- To explore SphK1's involvement in the S1P/S1PR3/Notch signaling pathway.
Main Methods:
- Quantified SphK1 levels in breast cancer tissues and cells.
- Utilized immunohistochemistry to assess HER2 and phosphor-SphK1 (pSphK1) expression.
- Performed Transwell assays to analyze metastasis potential and measured SphK1 activity, extracellular S1P, and analyzed associations with clinical parameters.
Main Results:
- SphK1 levels were significantly higher in TNBC patients compared to other breast tumor types.
- Elevated SphK1 expression correlated with poorer overall survival (OS) and progression-free survival (PFS).
- SphK1 inhibition repressed Notch signaling, reducing TNBC cell migration and invasion, and sensitized tumors to chemotherapy.
Conclusions:
- Elevated pSphK1 levels correlate with high S1P expression, promoting TNBC metastasis through the S1P/S1PR3/Notch signaling pathway.
- SphK1 inhibition represents a potential anti-tumor strategy by counteracting TNBC metastasis.
- Targeting SphK1 may improve treatment response to 5-FU and doxorubicin in TNBC.
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