Oncotarget

Research Papers:

SPHK1 regulates proliferation and survival responses in triple-negative breast cancer

Arpita Datta _, Ser Yue Loo, Baohua Huang, Lingkai Wong, Sheryl S.L. Tan, Tuan Zea Tan, Soo-Chin Lee, Jean Paul Thiery, Yaw Chyn Lim, Wei Peng Yong, Yulin Lam, Alan Prem Kumar, Celestial T. Yap

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Oncotarget. 2014; 5:5920-5933. https://doi.org/10.18632/oncotarget.1874

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Abstract

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 Lam6, Alan Prem Kumar2,5,8,10,11, Celestial T. Yap1,8

1 Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore

2 Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore

3 Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore

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 of Singapore, 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

Correspondence:

Celestial T. Yap, email:

Alan Prem Kumar, email:

Yulin Lam, email:

Keywords: sphingosine kinase, breast cancer, chemotherapy

Received: March 17, 2014 Accepted: March 27, 2014 Published: March 27, 2014

Abstract

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.


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