title: Breast cancer dissemination promoted by a neuregulin-collagenase 3 signalling node.
abstract: Advances in the treatment of breast cancer have resulted in increased survival. However, in the metastatic setting, the disease remains incurable. Therefore, understanding of the mechanisms that promote dissemination of breast cancer cells may favor the development of novel therapeutic strategies to fight those tumors. Here, we show that the ErbB ligands, Neuregulins (NRGs), promote metastatic dissemination of breast cancer cells by switching on a kinase-metalloproteinase network. Clinicopathological analyses demonstrated that NRG expression in breast tumors associated to lymph node invasion and poor patient outcome. Preclinical in vivo analyses showed that NRG expression favored in situ tumor growth, local spreading and metastatic dissemination. Genomic, biochemical and functional studies identified matrix metalloproteinases, particularly stromelysin 2 and collagenase 3, as key mediators of the NRG-induced dissemination properties of breast cancer cells. Mechanistic analyses demonstrated that NRG augmented metalloproteinase expression through a route controlled by ERK1/2 kinases. ERK1/2 increased collagenase 3 expression by controlling the activity of an SBF1-related transcription factor. In conclusion, we describe a pathway linked to breast cancer dissemination. The clinical availability of agents that target some of the components of this signalling pathway suggests that patients with tumors fed by NRGs or other factors able to activate the ERK-Collagenase 3 route may benefit from agents that act on that signalling axis.
authors.affiliation: Instituto de Biología Molecular y Celular del Cáncer, CSIC-Universidad de Salamanca, Salamanca, Spain.
authors.forename: S
authors.initials: S
authors.lastname: Seoane
authors.affiliation: Instituto de Biología Molecular y Celular del Cáncer, CSIC-Universidad de Salamanca, Salamanca, Spain.
authors.forename: J C
authors.initials: JC
authors.lastname: Montero
authors.affiliation: Servicio de Oncología Médica, Complejo Hospitalario Universitario de Albacete, and AECC Unit, Albcete, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Ocaña
authors.affiliation: Instituto de Biología Molecular y Celular del Cáncer, CSIC-Universidad de Salamanca, Salamanca, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Pandiella
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D018572:Disease-Free Survival; D005260:Female; D064593:Heterografts; D006801:Humans; D061986:MCF-7 Cells; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism*; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D020880:Neuregulins / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D020880:Neuregulins; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D053509:Matrix Metalloproteinase 13