SPHK1 expression in TNBC tumors and cell-lines. SPHK1 overexpression increase metastatic related properties. SPHK1 knockdown has no significant difference in cell proliferation but decrease invasion and migration potential in vitro. SPHK1 knockdown has no significant difference in tumor cell proliferation but increase apoptosis. Correlation between SPHK1 and FSCN1 expression. Ectopic expression of FSCN1 rescue the invasive and migrative potential of SPHK1 knockdown cells in vitro. FSCN1 knockdown decreased metastasis related properties in vitro. SPHK1 plays role in increasing the transcriptional rate of the FSCN1 gene transcription but not the mRNA stability. Safingol and Bortezomib treatment on TNBC cells in vitro and in vivo. Inhibition of lung metastasis by safingol plus bortezomib combination treatment when primary tumors were removed at similar sizes.
ARTICLE ABSTRACT
Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype. To identify TNBC therapeutic targets, we performed integrative bioinformatics analysis of multiple breast cancer patient-derived gene expression datasets and focused on kinases with FDA-approved or in-pipeline inhibitors. Sphingosine kinase 1 (SPHK1) was identified as a top candidate. SPHK1 overexpression or downregulation in human TNBC cell lines increased or decreased spontaneous metastasis to lungs in nude mice, respectively. SPHK1 promoted metastasis by transcriptionally upregulating the expression of the metastasis-promoting gene FSCN1 via NFκB activation. Activation of the SPHK1/NFκB/FSCN1 signaling pathway was associated with distance metastasis and poor clinical outcome in patients with TNBC. Targeting SPHK1 and NFκB using clinically applicable inhibitors (safingol and bortezomib, respectively) significantly inhibited aggressive mammary tumor growth and spontaneous lung metastasis in orthotopic syngeneic TNBC mouse models. These findings highlight SPHK1 and its downstream target, NFκB, as promising therapeutic targets in TNBC.
SPHK1 is overexpressed in TNBC and promotes metastasis, targeting SPHK1 or its downstream target NFκB with clinically available inhibitors could be effective for inhibiting TNBC metastasis.