title: CX3CL1 promotes breast cancer via transactivation of the EGF pathway.
abstract: Chemokines are relevant molecules in shaping the tumor microenvironment, although their contributions to tumorigenesis are not fully understood. We studied the influence of the chemokine CX3CL1/fractalkine in de novo breast cancer formation using HER2/neu transgenic mice. CX3CL1 expression was downmodulated in HER2/neu tumors, yet, paradoxically, adenovirus-mediated CX3CL1 expression in the tumor milieu enhanced mammary tumor numbers in a dose-dependent manner. Increased tumor multiplicity was not a consequence of CX3CL1-induced metastatic dissemination of the primary tumor, although CX3CL1 induced epithelial-to-mesenchymal transition in breast cancer cells in vitro. Instead, CX3CL1 triggered cell proliferation by induction of ErbB receptors through the proteolytic shedding of an ErbB ligand. This effect was important insofar as mammary tumorigenesis was delayed and tumor multiplicity was reduced by genetic deletion of CX3CL1 in HER2/neu mice, but not in polyoma middle T-antigen oncomice. Our findings support the conclusion that CX3CL1 acts as a positive modifier of breast cancer in concert with ErbB receptors.
authors.affiliation: Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Madrid, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Tardáguila
authors.forename: Emilia
authors.initials: E
authors.lastname: Mira
authors.forename: Miguel A
authors.initials: MA
authors.lastname: García-Cabezas
authors.forename: Anna M
authors.initials: AM
authors.lastname: Feijoo
authors.forename: Miguel
authors.initials: M
authors.lastname: Quintela-Fandino
authors.forename: Iñigo
authors.initials: I
authors.lastname: Azcoitia
authors.forename: Sergio A
authors.initials: SA
authors.lastname: Lira
authors.forename: Santos
authors.initials: S
authors.lastname: Mañes
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism*; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D054428:Chemokine CX3CL1 / Q000235:genetics* / Q000378:metabolism*; D004815:Epidermal Growth Factor / Q000235:genetics / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D005260:Female; D006801:Humans; D008198:Lymph Nodes / Q000378:metabolism / Q000473:pathology; D008207:Lymphatic Metastasis; D061986:MCF-7 Cells; D008321:Mammary Glands, Animal / Q000378:metabolism; D015674:Mammary Neoplasms, Animal; D008325:Mammary Neoplasms, Experimental; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D015533:Transcriptional Activation
chemical_list: D054428:Chemokine CX3CL1; D004815:Epidermal Growth Factor; D018719:Erb-b2 Receptor Tyrosine Kinases; D019707:Receptors, Chemokine