CXCL16/CXCR6 chemokine signaling mediates breast cancer progression by pERK1/2-dependent mechanisms

Abstract

Our previous studies demonstrate that CXCL6/CXCR6 chemokine axis induces prostate cancer progression by the AKT/mTOR signaling pathway; however, its role and mechanisms underlying invasiveness and metastasis of breast cancer are yet to be elucidated. In this investigation, CXCR6 protein expression was examined using high-density tissue microarrays and immunohistochemistry. Expression of CXCR6 shows a higher epithelial staining in breast cancer nest site and metastatic lymph node than the normal breast tissue, suggesting that CXCR6 may be involved in breast cancer (BC) development. In vitro and in vivo experiments indicate that overexpression of CXCR6 in BC cells has a marked effect on increasing cell migration, invasion and metastasis. In contrast, reduction of CXCR6 expression by shRNAs in these cells greatly reduce its invasion and metastasis ability. Mechanistic analyses show that CXCL16/CXCR6 chemokine axis is capable of modulating activation of RhoA through activating ERK1/2 signaling pathway, which then inhibits the activity of cofilin, thereby enhancing the stability of F-actin, responsible for invasiveness and metastasis of BC.Taken together, our data shows for the first time that the CXCR6 / ERK1/2/ RhoA / cofilin /F-actin pathway plays a central role in the development of BC. Targeting the signaling pathway may prove beneficial to prevent metastasis and provide a more effective therapeutic strategy for BC.

Identification of Potential Therapeutic Targets Among CXC Chemokines in Breast Tumor Microenvironment Using Integrative Bioinformatics Analysis

“…CXCR6 was found not only in stromal cells but was also constitutively expressed in cancer cells. BC cells mediate production of autocrine CXCL16, promoting cancer progression via pERK1/2 signaling [63]. On the other hand, stromal cells like CAFs can secrete CXCL16, a chemoattractant for monocytes that contributes to the aggressive phenotype of TNBC [64].…”

Basal-like breast cancer: molecular profiles, clinical features and survival outcomes

“…In other reports, the CXCR6 over-expression has been linked to TNBCs, with distinct roles in autoimmunity and cancer [56]. The co-expression of CXCR6 and CXCL16 , a chemokine ligand and receptor, has been associated with inflammatory response and cell migration [57, 58]. In addition, high levels of HCST [59, 60], C3AR1 [61], GBP4 [62], LY96 [63], ANKRD22 [64], FPR3 [65] and FCGR2A [66], have also been related to immune activation and/or inflammatory response in tumours; however, their role in basal-like breast malignancies are yet to be uncovered.…”

Inferring miRNA sponge co-regulation of protein-protein interactions in human breast cancer

“…3, 9 out of 17 modules are significantly enriched in 26 KEGG pathways. Several enriched KEGG pathways are associated with breast cancer, such as Cell cycle [50], TGF-beta signaling pathway [51], Pathways in cancer, Hippo signaling pathway [52], Ras signalling pathway [53], ErbB signaling pathway [54], Chemokine signalling pathway [55], and Calcium signalling pathway [56]. Specifically, three modules (M2, M3, and M4) are significantly involved in the KEGG pathway: Breast cancer, suggesting that the three BRCA-related miRSCoPPI modules are closely associated with breast cancer.

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