title: Functional and prognostic significance of the genomic amplification of frizzled 6 (FZD6) in breast cancer.
abstract: Frizzled receptors mediate Wnt ligand signalling, which is crucially involved in regulating tissue development and differentiation, and is often deregulated in cancer. In this study, we found that the gene encoding the Wnt receptor frizzled 6 (FZD6) is frequently amplified in breast cancer, with an increased incidence in the triple-negative breast cancer (TNBC) subtype. Ablation of FZD6 expression in mammary cancer cell lines: (1) inhibited motility and invasion; (2) induced a more symmetrical shape of organoid three-dimensional cultures; and (3) inhibited bone and liver metastasis in vivo. Mechanistically, FZD6 signalling is required for the assembly of the fibronectin matrix, interfering with the organization of the actin cytoskeleton. Ectopic delivery of fibronectin in FZD6-depleted, triple-negative MDA-MB-231 cells rearranged the actin cytoskeleton and restored epidermal growth factor-mediated invasion. In patients with localized, lymph node-negative (early) breast cancer, positivity of tumour cells for FZD6 protein identified patients with reduced distant relapse-free survival. Multivariate analysis indicated an independent prognostic significance of FZD6 expression in TNBC tumours, predicting distant, but not local, relapse. We conclude that the FZD6-fibronectin actin axis identified in our study could be exploited for drug development in highly metastatic forms of breast cancer, such as TNBC. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
authors.affiliation: College of Health and Life Sciences, Brunel University London, Uxbridge, UK.|Institute of Environment, Health and Societies, Brunel University London, Uxbridge, UK.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Corda
authors.affiliation: MediaPharma srl, Chieti, Italy.|Dipartimento di Scienze Mediche, Orali e Biotecnologiche, CESI-MeT, University G. D'Annunzio, Chieti, Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Sala
authors.affiliation: Dipartimento di Scienze Mediche, Orali e Biotecnologiche, CESI-MeT, University G. D'Annunzio, Chieti, Italy.
authors.forename: Rossano
authors.initials: R
authors.lastname: Lattanzio
authors.affiliation: Dipartimento di Medicina e Scienze dell'Invecchiamento, CESI-MeT, University G. D'Annunzio, Chieti, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Iezzi
authors.affiliation: Dipartimento di Scienze Mediche, Orali e Biotecnologiche, CESI-MeT, University G. D'Annunzio, Chieti, Italy.|Fondazione Mario Negri Sud, S. Maria Imbaro, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Sallese
authors.affiliation: Dipartimento di Scienze Mediche, Orali e Biotecnologiche, CESI-MeT, University G. D'Annunzio, Chieti, Italy.|Fondazione Mario Negri Sud, S. Maria Imbaro, Italy.
authors.forename: Giorgia
authors.initials: G
authors.lastname: Fragassi
authors.affiliation: Dipartimento di Medicina e Scienze dell'Invecchiamento, CESI-MeT, University G. D'Annunzio, Chieti, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Lamolinara
authors.affiliation: Breast Cancer Now Unit, Research Oncology, King's Health Partners AHSC, Faculty of Life Sciences and Medicine, King's College London, London, UK.
authors.forename: Hasan
authors.initials: H
authors.lastname: Mirza
authors.affiliation: Dipartimento di Scienze Psicologiche, della Salute e del Territorio, CESI-MeT, University G. D'Annunzio, Chieti, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Barcaroli
authors.affiliation: College of Health and Life Sciences, Brunel University London, Uxbridge, UK.|Institute of Environment, Health and Societies, Brunel University London, Uxbridge, UK.
authors.forename: Sibylle
authors.initials: S
authors.lastname: Ermler
authors.affiliation: College of Health and Life Sciences, Brunel University London, Uxbridge, UK.|Institute of Environment, Health and Societies, Brunel University London, Uxbridge, UK.
authors.forename: Elisabete
authors.initials: E
authors.lastname: Silva
authors.affiliation: College of Health and Life Sciences, Brunel University London, Uxbridge, UK.
authors.forename: Hemad
authors.initials: H
authors.lastname: Yasaei
authors.affiliation: College of Health and Life Sciences, Brunel University London, Uxbridge, UK.|Institute of Environment, Health and Societies, Brunel University London, Uxbridge, UK.
authors.forename: Robert F
authors.initials: RF
authors.lastname: Newbold
authors.affiliation: College of Health and Life Sciences, Brunel University London, Uxbridge, UK.|Institute of Environment, Health and Societies, Brunel University London, Uxbridge, UK.
authors.forename: Paola
authors.initials: P
authors.lastname: Vagnarelli
authors.affiliation: Regina Elena Cancer Institute, Rome, Italy.
authors.forename: Marcella
authors.initials: M
authors.lastname: Mottolese
authors.affiliation: MediaPharma srl, Chieti, Italy.
authors.forename: Pier Giorgio
authors.initials: PG
authors.lastname: Natali
authors.affiliation: Regina Elena Cancer Institute, Rome, Italy.
authors.forename: Letizia
authors.initials: L
authors.lastname: Perracchio
authors.affiliation: Breast Cancer Now Unit, Research Oncology, King's Health Partners AHSC, Faculty of Life Sciences and Medicine, King's College London, London, UK.
authors.forename: Jelmar
authors.initials: J
authors.lastname: Quist
authors.affiliation: Breast Cancer Now Unit, Research Oncology, King's Health Partners AHSC, Faculty of Life Sciences and Medicine, King's College London, London, UK.
authors.forename: Anita
authors.initials: A
authors.lastname: Grigoriadis
authors.affiliation: Breast Cancer Now Unit, Research Oncology, King's Health Partners AHSC, Faculty of Life Sciences and Medicine, King's College London, London, UK.
authors.forename: Pierfrancesco
authors.initials: P
authors.lastname: Marra
authors.affiliation: Breast Cancer Now Unit, Research Oncology, King's Health Partners AHSC, Faculty of Life Sciences and Medicine, King's College London, London, UK.|Breast Cancer Now, The Institute of Cancer Research, London, UK.
authors.forename: Andrew N
authors.initials: AN
authors.lastname: Tutt
authors.affiliation: Dipartimento di Scienze Mediche, Orali e Biotecnologiche, CESI-MeT, University G. D'Annunzio, Chieti, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Piantelli
authors.affiliation: MediaPharma srl, Chieti, Italy.|Dipartimento di Scienze Mediche, Orali e Biotecnologiche, CESI-MeT, University G. D'Annunzio, Chieti, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Iacobelli
authors.affiliation: Dipartimento di Scienze Mediche, Orali e Biotecnologiche, CESI-MeT, University G. D'Annunzio, Chieti, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: De Laurenzi
authors.affiliation: College of Health and Life Sciences, Brunel University London, Uxbridge, UK.|Institute of Environment, Health and Societies, Brunel University London, Uxbridge, UK.|Dipartimento di Scienze Psicologiche, della Salute e del Territorio, CESI-MeT, University G. D'Annunzio, Chieti, Italy.
authors.forename: Arturo
authors.initials: A
authors.lastname: Sala
mesh_terms: D001943:Breast Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D005260:Female; D051157:Frizzled Receptors / Q000235:genetics* / Q000378:metabolism; D023281:Genomics / Q000379:methods; D006801:Humans; D009364:Neoplasm Recurrence, Local / Q000235:genetics*; D011379:Prognosis; D015398:Signal Transduction / Q000235:genetics
chemical_list: C484687:FZD6 protein, human; D051157:Frizzled Receptors
keywords: Wnt signalling; actin cytoskeleton; metastasis; mouse model; xenograft