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.
Highlights
Specialty section: This article was submitted to Cancer Molecular Targets and Therapeutics, a section of the journal
High sphingosine kinase 1 (SK1) expression has been linked with poorer survival and prognosis
estrogen receptor (ER)-positive patients treated with tamoxifen (n = 304): – Nuclear SK1 expression is associated with shorter time to recurrence on tamoxifen and shorter disease-specific survival – High levels of cytoplasmic SK1 and cytoplasmic ERK1/2 are associated with shorter time to recurrence on tamoxifen – High membrane S1PR1 expression is associated with shorter time to recurrence – High cytoplasmic S1PR3 expression is associated with shorter disease-specific survival – Membrane and cytoplasmic S1PR3 expression correlated with progesterone receptor (PR) status and nuclear S1PR3 correlated with tumor size
Summary
S1P functional antagonist and SK1 inhibitor FTY720 in combination with doxorubicin is capable of suppressing inflammation induced by doxorubicin This combination inhibited growth of E0771 cells (a mouse mammary adenocarcinoma cell line expressing the ER) in vitro and suppressed the expression of S1P signaling-related genes, STAT3 and IL-6, as well as reducing tumor burden in vivo [119], suggesting that the SK1/S1P/S1PR1 axis plays a role in doxorubicin resistance. In patients with invasive ductal carcinoma, high SK1 expression was an independent factor for predicting shorter recurrence-free survival and was significantly associated with more aggressive oncogenic behavior, including higher histological grade, development of distant metastasis, negativity for estrogen, progesterone and HER2 receptors, and triple negativity [91].
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
