Triple-negative breast cancer (TNBC) is characterized by unique aggressive behavior and lack of targeted therapies. Among the various molecular subtypes of breast cancer, it was observed that TNBCs express elevated levels of sphingosine kinase 1 (SPHK1) compared to other breast tumor subtypes. High levels of SPHK1 gene expression correlated with poor overall and progression- free survival, as well as poor response to Doxorubicin-based treatment. Inhibition of SPHK1 was found to attenuate ERK1/2 and AKT signaling and reduce growth of TNBC cells in vitro and in a xenograft SCID mouse model. Moreover, SPHK1 inhibition by siRNA knockdown or treatment with SKI-5C sensitizes TNBCs to chemotherapeutic drugs. Our findings suggest that SPHK1 inhibition, which effectively counteracts oncogenic signaling through ERK1/2 and AKT pathways, is a potentially important anti-tumor strategy in TNBC. A combination of SPHK1 inhibitors with chemotherapeutic agents may be effective against this aggressive subtype of breast cancer.
Figure 1:SPHK1 expression in breast tumors. (A) SPHK1mRNA expression in human breast tumors and paired adjacent normal breast tissues by real-time PCR. Expression levels were normalized with GAPDH. A two-tailed Student t-test was used to calculate statistical significance. (B) SPHK1 mRNA expression in ER-positive, ER (+), and ER-negative, ER (-) cases. Each dot corresponds to an individual patient’s fold change in relative SPHK1 mRNA levels between tumor and adjacent normal tissue. ER (-) patients showed significantly higher expression of SPHK1 than ER (+) patients (p = 0.007). (C) SPHK1 gene expression levels in breast cancer subtypes. Basal subtype has the highest SPHK1 gene expression (Mann Whitney Test, p = 4.16e-81), whereas Luminal-A and –B subtypes have the lowest SPHK1 gene expression (Mann Whitney Test, p = 1.1e-21, and p = 6.74e-37, respectively). (D) SPHK1 gene expression correlates with poor overall (left) and progression-free survival (right). Kaplan-Meier plots of overall and progression-free survival in all samples. Median expression was used to define SPHK1-Low and SPHK1-High. The p-value shown was computed by log-rank test. HR indicates the hazard ratio, and n in parentheses indicates number of samples.
Arpita Datta1, Ser Yue Loo1,2,3,5, Baohua Huang1, Lingkai Wong6, Sheryl S.L. Tan1, Tuan Zea Tan5, Soo-Chin Lee5,7,8, Jean Paul Thiery3,5,8,9, Yaw Chyn Lim1,4, Wei Peng Yong5,7,8, Yulin Lam3,*, Alan Prem Kumar2,5,8,10,11,*, Celestial T. Yap1,8,*
1 Department of Physiology; 2 Department of Pharmacology; 3 Department of Biochemistry; 4 Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore
5 Cancer Science Institute of Singapore, National University of Singapore
6 Department of Chemistry, National University Hospital, Singapore
7 Department of Haematology-Oncology, National University Hospital, Singapore
8 National University Cancer Institute, Singapore;
9 Institute of Molecular and Cell Biology (IMCB), A*STAR, Singapore
10 School of Biomedical Sciences, Faculty of Health Sciences, Curtin University, Western Australia
11 Department of Biological Sciences, University of North Texas, Denton, Texas, USA
Celestial T. Yap, email: phsyapc[a]nus.edu.sg
Alan Prem Kumar, email: csiapk[at]nus.edu.sg
Yulin Lam, email: chmlamyl[a]nus.edu.sg