title: 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.
authors.affiliation: Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Xiao
authors.affiliation: Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Xiumin
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Jinglong
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Lidong
authors.initials: L
authors.lastname: Zu
authors.affiliation: Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Guangcun
authors.initials: G
authors.lastname: Cheng
authors.affiliation: Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Mingang
authors.initials: M
authors.lastname: Hao
authors.affiliation: Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Xueqing
authors.initials: X
authors.lastname: Sun
authors.affiliation: Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Yunjing
authors.initials: Y
authors.lastname: Xue
authors.affiliation: Comprehensive Breast Health Center, Renji Hospital, Shanghai, China.
authors.forename: Jinsong
authors.initials: J
authors.lastname: Lu
authors.affiliation: Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, China.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Wang
mesh_terms: D051339:Actin Depolymerizing Factors / Q000378:metabolism; D000199:Actins / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D000075743:Chemokine CXCL16; D019743:Chemokines, CXC / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D018450:Disease Progression; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D010766:Phosphorylation; D000075744:Receptors, CXCR6; D019707:Receptors, Chemokine / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D051116:Receptors, Scavenger / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D011991:Receptors, Virus / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D051339:Actin Depolymerizing Factors; D000199:Actins; C423727:CXCL16 protein, human; C106330:CXCR6 protein, human; D000075743:Chemokine CXCL16; D019743:Chemokines, CXC; D000075744:Receptors, CXCR6; D019707:Receptors, Chemokine; D051116:Receptors, Scavenger; D011991:Receptors, Virus; C066737:RHOA protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020742:rhoA GTP-Binding Protein
keywords: CXCL16/CXCR6; ERK1/2; RhoA; breast cancer