title: The CDC42-interacting protein 4 controls epithelial cell cohesion and tumor dissemination.
abstract: The role of endocytic proteins and the molecular mechanisms underlying epithelial cell cohesion and tumor dissemination are not well understood. Here, we report that the endocytic F-BAR-containing CDC42-interacting protein 4 (CIP4) is required for ERBB2- and TGF-β1-induced cell scattering, breast cancer (BC) cell motility and invasion into 3D matrices, and conversion from ductal breast carcinoma in situ to invasive carcinoma in mouse xenograft models. CIP4 promotes the formation of an E-cadherin-CIP4-SRC complex that controls SRC activation, E-cadherin endocytosis, and localized phosphorylation of the myosin light chain kinase, thereby impinging on the actomyosin contractility required to generate tangential forces to break cell-cell junctions. CIP4 is upregulated in ERBB2-positive human BC, correlates with increased distant metastasis, and is an independent predictor of poor disease outcome in subsets of BC patients. Thus, it critically controls cell-cell cohesion and is required for the acquisition of an invasive phenotype in breast tumors.
authors.affiliation: IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Via Adamello 16, 20139 Milan, Italy.
authors.forename: Yannève
authors.initials: Y
authors.lastname: Rolland
authors.affiliation: IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Via Adamello 16, 20139 Milan, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Marighetti
authors.affiliation: IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Via Adamello 16, 20139 Milan, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Malinverno
authors.affiliation: IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Via Adamello 16, 20139 Milan, Italy; Dipartimento di Oncologia Sperimentale, Istituto Europeo di Oncologia, 20141 Milan, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Confalonieri
authors.affiliation: IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Via Adamello 16, 20139 Milan, Italy; Dipartimento di Oncologia Sperimentale, Istituto Europeo di Oncologia, 20141 Milan, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Luise
authors.affiliation: Dipartimento di Scienze Oncologiche, Università degli Studi di Torino, Istituto per la Ricerca e la Cura del Cancro, Strada Provinciale 142 10060 Candiolo, Turin, Italy.
authors.forename: Nadia
authors.initials: N
authors.lastname: Ducano
authors.affiliation: IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Via Adamello 16, 20139 Milan, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Palamidessi
authors.affiliation: IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Via Adamello 16, 20139 Milan, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Bisi
authors.affiliation: IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Via Adamello 16, 20139 Milan, Italy.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Kajiho
authors.affiliation: IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Via Adamello 16, 20139 Milan, Italy; Dipartimento di Oncologia Sperimentale, Istituto Europeo di Oncologia, 20141 Milan, Italy.
authors.forename: Flavia
authors.initials: F
authors.lastname: Troglio
authors.affiliation: Department of Chemical Engineering, Stanford University, Stanford, CA 94305, USA.
authors.forename: Olga G
authors.initials: OG
authors.lastname: Shcherbakova
authors.affiliation: Department of Chemical Engineering, Stanford University, Stanford, CA 94305, USA.
authors.forename: Alexander R
authors.initials: AR
authors.lastname: Dunn
authors.affiliation: IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Via Adamello 16, 20139 Milan, Italy.
authors.forename: Amanda
authors.initials: A
authors.lastname: Oldani
authors.affiliation: Dipartimento di Scienze Oncologiche, Università degli Studi di Torino, Istituto per la Ricerca e la Cura del Cancro, Strada Provinciale 142 10060 Candiolo, Turin, Italy.
authors.forename: Letizia
authors.initials: L
authors.lastname: Lanzetti
authors.affiliation: IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Via Adamello 16, 20139 Milan, Italy; Dipartimento di Oncologia Sperimentale, Istituto Europeo di Oncologia, 20141 Milan, Italy; Dipartimento di Scienze della Salute, San Paolo, Università degli Studi di Milano, 20122 Milan, Italy.
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Di Fiore
authors.affiliation: IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Via Adamello 16, 20139 Milan, Italy. Electronic address: andrea.disanza@ifom.eu.
authors.forename: Andrea
authors.initials: A
authors.lastname: Disanza
authors.affiliation: IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Via Adamello 16, 20139 Milan, Italy; Dipartimento di Scienze della Salute, San Paolo, Università degli Studi di Milano, 20122 Milan, Italy. Electronic address: giorgio.scita@ifom.eu.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Scita
mesh_terms: D000205:Actomyosin / Q000378:metabolism; D000818:Animals; D015820:Cadherins / Q000378:metabolism; D018270:Carcinoma, Ductal, Breast / Q000473:pathology; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000473:pathology; D045744:Cell Line, Tumor; D004705:Endocytosis; D004847:Epithelial Cells / Q000166:cytology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D015778:Minor Histocompatibility Antigens; D009368:Neoplasm Transplantation; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D064726:Triple Negative Breast Neoplasms / Q000378:metabolism*
chemical_list: D000205:Actomyosin; D015820:Cadherins; D008869:Microtubule-Associated Proteins; D015778:Minor Histocompatibility Antigens; D018719:Erb-b2 Receptor Tyrosine Kinases; D053773:Transforming Growth Factor beta1; C508960:TGFB1 protein, human; C406285:TRIP10 protein, human; C508961:Tgfb1 protein, mouse; C485787:Trip10 protein, mouse; C508053:ERBB2 protein, human; C524056:Erbb2 protein, mouse