title: Interaction of CDCP1 with HER2 enhances HER2-driven tumorigenesis and promotes trastuzumab resistance in breast cancer.
abstract: Understanding the molecular pathways that contribute to the aggressive behavior of HER2-positive breast cancers may aid in the development of novel therapeutic interventions. Here, we show that CDCP1 and HER2 are frequently co-overexpressed in metastatic breast tumors and associated with poor patient prognosis. HER2 and CDCP1 co-overexpression leads to increased transformation ability, cell migration, and tumor formation in vivo, and enhanced HER2 activation and downstream signaling in different breast cancer cell lines. Mechanistically, we demonstrate that CDCP1 binds to HER2 through its intracellular domain, thereby increasing HER2 interaction with the non-receptor tyrosine kinase c-SRC (SRC), leading to trastuzumab resistance. Taken together, our findings establish that CDCP1 is a modulator of HER2 signaling and a biomarker for the stratification of breast cancer patients with poor prognosis. Our results also provide a rationale for therapeutic targeting of CDCP1 in HER2-positive breast cancer patients.
authors.affiliation: Institute of Oncology Research (IOR), Bellinzona 6500, Switzerland; Oncology Institute of Southern Switzerland (IOSI), Bellinzona 6500, Switzerland.
authors.forename: Abdullah
authors.initials: A
authors.lastname: Alajati
authors.affiliation: Institute of Oncology Research (IOR), Bellinzona 6500, Switzerland; Oncology Institute of Southern Switzerland (IOSI), Bellinzona 6500, Switzerland.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Guccini
authors.affiliation: Institute of Oncology Research (IOR), Bellinzona 6500, Switzerland; Oncology Institute of Southern Switzerland (IOSI), Bellinzona 6500, Switzerland.
authors.forename: Sandra
authors.initials: S
authors.lastname: Pinton
authors.affiliation: Institute of Oncology Research (IOR), Bellinzona 6500, Switzerland; Molecular Oncology Unit, CIEMAT, Madrid 28040, Spain; Oncogenomics Unit, Institute of Biomed Research, Hospital "12 de Octubre", 28041 Madrid, Spain.
authors.forename: Ramon
authors.initials: R
authors.lastname: Garcia-Escudero
authors.affiliation: Institute of Oncology Research (IOR), Bellinzona 6500, Switzerland.
authors.forename: Tiziano
authors.initials: T
authors.lastname: Bernasocchi
authors.affiliation: Institute of Oncology Research (IOR), Bellinzona 6500, Switzerland; Oncology Institute of Southern Switzerland (IOSI), Bellinzona 6500, Switzerland.
authors.forename: Manuela
authors.initials: M
authors.lastname: Sarti
authors.affiliation: Institute for Research in Biomedicine (IRB), Bellinzona 6500, Switzerland.
authors.forename: Erica
authors.initials: E
authors.lastname: Montani
authors.affiliation: Institute of Oncology Research (IOR), Bellinzona 6500, Switzerland; Oncology Institute of Southern Switzerland (IOSI), Bellinzona 6500, Switzerland.
authors.forename: Andrea
authors.initials: A
authors.lastname: Rinaldi
authors.affiliation: Investigative Clinical Oncology (INCO), Fondazione del Piemonte per l'Oncologia Candiolo Cancer Institute (IRCCS), Strada Provinciale 142, 10060 Candiolo, Italy.
authors.forename: Filippo
authors.initials: F
authors.lastname: Montemurro
authors.affiliation: Institute of Oncology Research (IOR), Bellinzona 6500, Switzerland; Oncology Institute of Southern Switzerland (IOSI), Bellinzona 6500, Switzerland.
authors.forename: Carlo
authors.initials: C
authors.lastname: Catapano
authors.affiliation: Institute of Oncology Research (IOR), Bellinzona 6500, Switzerland; Oncology Institute of Southern Switzerland (IOSI), Bellinzona 6500, Switzerland.
authors.forename: Francesco
authors.initials: F
authors.lastname: Bertoni
authors.affiliation: Institute of Oncology Research (IOR), Bellinzona 6500, Switzerland; Oncology Institute of Southern Switzerland (IOSI), Bellinzona 6500, Switzerland; Faculty of Biology and Medicine, University of Lausanne UNIL, Lausanne 1011, Switzerland. Electronic address: andrea.alimonti@ior.iosi.ch.
authors.forename: Andrea
authors.initials: A
authors.lastname: Alimonti
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D000068878:Trastuzumab / Q000494:pharmacology; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D015815:Cell Adhesion Molecules; D009363:Neoplasm Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; D019061:src-Family Kinases; C432044:CDCP1 protein, human; C508053:ERBB2 protein, human