title: Oncogene-like induction of cellular invasion from centrosome amplification.
abstract: Centrosome amplification has long been recognized as a feature of human tumours; however, its role in tumorigenesis remains unclear. Centrosome amplification is poorly tolerated by non-transformed cells and, in the absence of selection, extra centrosomes are spontaneously lost. Thus, the high frequency of centrosome amplification, particularly in more aggressive tumours, raises the possibility that extra centrosomes could, in some contexts, confer advantageous characteristics that promote tumour progression. Using a three-dimensional model system and other approaches to culture human mammary epithelial cells, we find that centrosome amplification triggers cell invasion. This invasive behaviour is similar to that induced by overexpression of the breast cancer oncogene ERBB2 (ref. 4) and indeed enhances invasiveness triggered by ERBB2. Our data indicate that, through increased centrosomal microtubule nucleation, centrosome amplification increases Rac1 activity, which disrupts normal cell-cell adhesion and promotes invasion. These findings demonstrate that centrosome amplification, a structural alteration of the cytoskeleton, can promote features of malignant transformation.
authors.affiliation: 1] Howard Hughes Medical Institute, Department of Pediatric Oncology, Dana-Farber Cancer Institute and Pediatric Hematology/Oncology, Children's Hospital, Boston, Massachusetts 02115, USA [2] Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA [3] Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK (S.A.G.); Department of Pharmacology, University of Minnesota, Minneapolis, Minnesota 55455, USA (C.T.L.).
authors.forename: Susana A
authors.initials: SA
authors.lastname: Godinho
authors.affiliation: 1] Howard Hughes Medical Institute, Department of Pediatric Oncology, Dana-Farber Cancer Institute and Pediatric Hematology/Oncology, Children's Hospital, Boston, Massachusetts 02115, USA [2] Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Remigio
authors.initials: R
authors.lastname: Picone
authors.affiliation: 1] Institut de Recherche en Technologie et Science pour le Vivant, UMR5168 CEA/UJF/INRA/CNRS, Grenoble, France [2] Hôpital Saint Louis, Institut Universitaire d'Hematologie, U1160 INSERM/AP-HP/Université Paris Diderot, Paris 75010, France [3] CYTOO SA, Grenoble 38054, France.
authors.forename: Mithila
authors.initials: M
authors.lastname: Burute
authors.affiliation: 1] Howard Hughes Medical Institute, Department of Pediatric Oncology, Dana-Farber Cancer Institute and Pediatric Hematology/Oncology, Children's Hospital, Boston, Massachusetts 02115, USA [2] Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Regina
authors.initials: R
authors.lastname: Dagher
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Su
authors.affiliation: 1] Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA [2] Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK (S.A.G.); Department of Pharmacology, University of Minnesota, Minneapolis, Minnesota 55455, USA (C.T.L.).
authors.forename: Cheuk T
authors.initials: CT
authors.lastname: Leung
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Kornelia
authors.initials: K
authors.lastname: Polyak
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Joan S
authors.initials: JS
authors.lastname: Brugge
authors.affiliation: 1] Institut de Recherche en Technologie et Science pour le Vivant, UMR5168 CEA/UJF/INRA/CNRS, Grenoble, France [2] Hôpital Saint Louis, Institut Universitaire d'Hematologie, U1160 INSERM/AP-HP/Université Paris Diderot, Paris 75010, France.
authors.forename: Manuel
authors.initials: M
authors.lastname: Théry
authors.affiliation: 1] Howard Hughes Medical Institute, Department of Pediatric Oncology, Dana-Farber Cancer Institute and Pediatric Hematology/Oncology, Children's Hospital, Boston, Massachusetts 02115, USA [2] Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: David
authors.initials: D
authors.lastname: Pellman
mesh_terms: D000782:Aneuploidy; D001940:Breast / Q000166:cytology / Q000473:pathology; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology*; D002448:Cell Adhesion; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology*; D018385:Centrosome / Q000473:pathology*; D018450:Disease Progression; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000166:cytology / Q000473:pathology; D018734:Genes, erbB-2; D006801:Humans; D008870:Microtubules / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D009361:Neoplasm Invasiveness / Q000473:pathology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: D018719:Erb-b2 Receptor Tyrosine Kinases; D020830:rac1 GTP-Binding Protein; C107953:RAC1 protein, human
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