CXCR6-CXCL16 Axis Promotes Breast Cancer by Inducing Oncogenic Signaling

SIMPLE SUMMARY: Breast cancer (BrCa) is the second leading cause of cancer-related deaths in American women, and its incidence is on the rise. Insufficient understanding of the mechanisms leading to BrCa limits the effectiveness of the treatment. In this article, we show the importance of a chemokine axis-CXCR6/CXCL16 in supporting BrCa progression. We have delineated BrCa-promoting mechanisms induced by this chemokine axis at the molecular level. This work projects the therapeutic significance of CXCR6/CXCL16 signaling for the treatment of BrCa. ABSTRACT: Precise mechanisms underlying breast cancer (BrCa) metastasis are undefined, which becomes a challenge for effective treatments. Chemokine signaling instigates the trafficking of cancer cells in addition to leukocytes. This study aimed to ascertain the clinical and biological significance of the CXCR6/CXCL16 signaling axis in the pathobiology of BrCa. Our data show a higher expression of CXCR6 in BrCa cell lines and tissues. Stage-III BrCa tissues express significantly higher CXCR6 compared to stage-II tissues. The ligand, CXCL16, could remain tethered to the cell surface, and, after proteolytic shedding of the ectodomain, the N-terminal fragment is released, converting it to its oncogenic, soluble form. Like CXCR6, N-terminal CXCL16 and ADAM-10 were significantly higher in stage-III than stage-II, but no significant difference was observed in the C-terminal fragment of CXCL16. Further, stimulation of the CXCR6/CXCL16 axis activated Src, FAK, ERK1/2, and PI3K signaling pathways, as per antibody microarray analysis, which also underlie CXCL16-induced F-actin polymerization. The CXCR6/CXCL16 axis induces cytoskeleton rearrangement facilitating migration and invasion and supports BrCa cell survival by activating the PI3K/Akt pathway. This study highlights the significance of the CXCR6/CXCL16 axis and ADAM10 as potential therapeutic targets for advanced-stage BrCa.