Journal
ONCOTARGET
Volume 5, Issue 15, Pages 5920-5933Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.1874
Keywords
sphingosine kinase; breast cancer; chemotherapy
Categories
Funding
- Biomedical Medical Research Council (BMRC)
- National Medical Research Council (NMRC)
- Ministry of Education
- Experimental Therapeutics 1 Program at the Cancer Science Institute
- National University of Singapore Academic Research Fund (NUS ARF)
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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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