Sphingosine Kinase 1 in Breast Cancer—A New Molecular Marker and a Therapy Target

Alshaker, Heba, Thrower, Hannah and Pchejetski, Dmitri (2020) Sphingosine Kinase 1 in Breast Cancer—A New Molecular Marker and a Therapy Target. Frontiers in Oncology, 10. ISSN 2234-943X

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Abstract

It is now well-established that sphingosine kinase 1 (SK1) plays a significant role in breast cancer development, progression, and spread, whereas SK1 knockdown can reverse these processes. In breast cancer cells and tumors, SK1 was shown to interact with various pathways involved in cell survival and chemoresistance, such as nuclear factor-kappa B (NFκB), Notch, Ras/MAPK, PKC, and PI3K. SK1 is upregulated by estrogen signaling, which, in turn, confers cancer cells with resistance to tamoxifen. Sphingosine-1-phosphate (S1P) produced by SK1 has been linked to tumor invasion and metastasis. Both SK1 and S1P are closely linked to inflammation and adipokine signaling in breast cancer. In human tumors, high SK1 expression has been linked with poorer survival and prognosis. SK1 is upregulated in triple negative tumors and basal-like subtypes. It is often associated with high phosphorylation levels of ERK1/2, SFK, LYN, AKT, and NFκB. Higher tumor SK1 mRNA levels were correlated with poor response to chemotherapy. This review summarizes the up-to-date evidence and discusses the therapeutic potential for the SK1 inhibition in breast cancer, with emphasis on the mechanisms of chemoresistance and combination with other therapies such as gefitinib or docetaxel. We have outlined four key areas for future development, including tumor microenvironment, combination therapies, and nanomedicine. We conclude that SK1 may have a potential as a target for precision medicine, its high expression being a negative prognostic marker in ER-negative breast cancer, as well as a target for chemosensitization therapy.

Item Type: Article
Additional Information: Copyright © 2020 Alshaker, Thrower and Pchejetski.
Uncontrolled Keywords: sphingolipids,sphingosine kinase 1,breast cancer,progression,chemoresistance,targeted therapy,molecular marker,sphingolipid metabolism,adjuvant chemotherapy,proteasomal-degradation,1-phosphate receptors,american-society,prognostic value,egf receptor,follow-up,expression,estrogen,oncology,cancer research ,/dk/atira/pure/subjectarea/asjc/2700/2730
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
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Depositing User: LivePure Connector
Date Deposited: 25 Apr 2020 00:03
Last Modified: 11 Jul 2020 00:10
URI: https://ueaeprints.uea.ac.uk/id/eprint/74837
DOI: 10.3389/fonc.2020.00289

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