Sphingosine-kinase-1 pathway offers positive therapeutic targets in triple-negative breast cancer for effective inhibition of metastasis

We identified sphingosine kinase 1 (SPHK1) as a top candidate. SPHK1-overexpression in human TNBC cell-line promotes spontaneous metastasis to lungs in nude mice. Moreover, genetic knockdown of SPHK1 in TNBC patient-derived xenograft (PDX) cells and TNBC cell-line decreases spontaneous metastasis to lungs in nude mice. SPHK1 regulates the FSCN1 gene expression in order to drive metastasis. Mechanistically, SPHK1 transcriptionally upregulates metastasis-promoting FSCN1 gene expression via NFκB activation to promote metastasis. SPHK1/NFκB/FSCN1 signaling pathway activation is associated with distance metastasis and poor clinical outcome in TNBC patients. MDA-MB-435 breast cancer cell lines (shRNA control and SPHK1 knockdown lines) were injected under mouse mammary fat pad (MFP). Spontaneous lung metastases were harvested and compared with MFP samples.