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

Oncotarget. 2015 Jun 10;6(16):14165-78. doi: 10.18632/oncotarget.3690.


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.

Keywords: CXCL16/CXCR6; ERK1/2; RhoA; breast cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actin Depolymerizing Factors / metabolism
  • Actins / metabolism
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Cell Movement / physiology
  • Chemokine CXCL16
  • Chemokines, CXC / biosynthesis
  • Chemokines, CXC / genetics
  • Chemokines, CXC / metabolism*
  • Disease Progression
  • Female
  • Humans
  • MCF-7 Cells
  • Mitogen-Activated Protein Kinase 1 / genetics
  • Mitogen-Activated Protein Kinase 1 / metabolism*
  • Mitogen-Activated Protein Kinase 3 / genetics
  • Mitogen-Activated Protein Kinase 3 / metabolism*
  • Neoplasm Invasiveness
  • Phosphorylation
  • Receptors, CXCR6
  • Receptors, Chemokine / biosynthesis
  • Receptors, Chemokine / genetics
  • Receptors, Chemokine / metabolism*
  • Receptors, Scavenger / biosynthesis
  • Receptors, Scavenger / genetics
  • Receptors, Scavenger / metabolism*
  • Receptors, Virus / biosynthesis
  • Receptors, Virus / genetics
  • Receptors, Virus / metabolism*
  • Signal Transduction
  • rhoA GTP-Binding Protein / metabolism


  • Actin Depolymerizing Factors
  • Actins
  • CXCL16 protein, human
  • CXCR6 protein, human
  • Chemokine CXCL16
  • Chemokines, CXC
  • Receptors, CXCR6
  • Receptors, Chemokine
  • Receptors, Scavenger
  • Receptors, Virus
  • RHOA protein, human
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • rhoA GTP-Binding Protein