title: Targeting ErbB-2 nuclear localization and function inhibits breast cancer growth and overcomes trastuzumab resistance.
abstract: Membrane overexpression of ErbB-2/HER2 receptor tyrosine kinase (membrane ErbB-2 (MErbB-2)) has a critical role in breast cancer (BC). We and others have also shown the role of nuclear ErbB-2 (NErbB-2) in BC, whose presence we identified as a poor prognostic factor in MErbB-2-positive tumors. Current anti-ErbB-2 therapies, as with the antibody trastuzumab (Ttzm), target only MErbB-2. Here, we found that blockade of NErbB-2 action abrogates growth of BC cells, sensitive and resistant to Ttzm, in a scenario in which ErbB-2, ErbB-3 and Akt are phosphorylated, and ErbB-2/ErbB-3 dimers are formed. Also, inhibition of NErbB-2 presence suppresses growth of a preclinical BC model resistant to Ttzm. We showed that at the cyclin D1 promoter, ErbB-2 assembles a transcriptional complex with Stat3 (signal transducer and activator of transcription 3) and ErbB-3, another member of the ErbB family, which reveals the first nuclear function of ErbB-2/ErbB-3 dimer. We identified NErbB-2 as the major proliferation driver in Ttzm-resistant BC, and demonstrated that Ttzm inability to disrupt the Stat3/ErbB-2/ErbB-3 complex underlies its failure to inhibit growth. Furthermore, our results in the clinic revealed that nuclear interaction between ErbB-2 and Stat3 correlates with poor overall survival in primary breast tumors. Our findings challenge the paradigm of anti-ErbB-2 drug design and highlight NErbB-2 as a novel target to overcome Ttzm resistance.
authors.affiliation: Laboratory of Molecular Mechanisms of Carcinogenesis, Instituto de Biología y Medicina Experimental (IBYME), CONICET, Buenos Aires, Argentina.
authors.forename: R I
authors.initials: RI
authors.lastname: Cordo Russo
authors.affiliation: Laboratory of Molecular Mechanisms of Carcinogenesis, Instituto de Biología y Medicina Experimental (IBYME), CONICET, Buenos Aires, Argentina.
authors.forename: W
authors.initials: W
authors.lastname: Béguelin
authors.affiliation: Laboratory of Molecular Mechanisms of Carcinogenesis, Instituto de Biología y Medicina Experimental (IBYME), CONICET, Buenos Aires, Argentina.
authors.forename: M C
authors.initials: MC
authors.lastname: Díaz Flaqué
authors.affiliation: Laboratory of Molecular Mechanisms of Carcinogenesis, Instituto de Biología y Medicina Experimental (IBYME), CONICET, Buenos Aires, Argentina.
authors.forename: C J
authors.initials: CJ
authors.lastname: Proietti
authors.affiliation: Laboratory of Molecular Mechanisms of Carcinogenesis, Instituto de Biología y Medicina Experimental (IBYME), CONICET, Buenos Aires, Argentina.
authors.forename: L
authors.initials: L
authors.lastname: Venturutti
authors.affiliation: Laboratory of Molecular Mechanisms of Carcinogenesis, Instituto de Biología y Medicina Experimental (IBYME), CONICET, Buenos Aires, Argentina.
authors.forename: N
authors.initials: N
authors.lastname: Galigniana
authors.affiliation: Laboratory of Molecular Mechanisms of Carcinogenesis, Instituto de Biología y Medicina Experimental (IBYME), CONICET, Buenos Aires, Argentina.
authors.forename: M
authors.initials: M
authors.lastname: Tkach
authors.affiliation: Departamento de Anatomía Patológica (BIOREN), Universidad de La Frontera, Temuco, Chile.
authors.forename: P
authors.initials: P
authors.lastname: Guzmán
authors.affiliation: Departamento de Anatomía Patológica (BIOREN), Universidad de La Frontera, Temuco, Chile.
authors.forename: J C
authors.initials: JC
authors.lastname: Roa
authors.affiliation: Department of Medicine, Division of Hematology/Oncology, Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
authors.forename: N A
authors.initials: NA
authors.lastname: O'Brien
authors.affiliation: Laboratory of Molecular Mechanisms of Carcinogenesis, Instituto de Biología y Medicina Experimental (IBYME), CONICET, Buenos Aires, Argentina.
authors.forename: E H
authors.initials: EH
authors.lastname: Charreau
authors.affiliation: Laboratory of Molecular Mechanisms of Carcinogenesis, Instituto de Biología y Medicina Experimental (IBYME), CONICET, Buenos Aires, Argentina.
authors.forename: R
authors.initials: R
authors.lastname: Schillaci
authors.affiliation: Laboratory of Molecular Mechanisms of Carcinogenesis, Instituto de Biología y Medicina Experimental (IBYME), CONICET, Buenos Aires, Argentina.
authors.forename: P V
authors.initials: PV
authors.lastname: Elizalde
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects* / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D004357:Drug Synergism; D005260:Female; D005799:Genes, Dominant / Q000502:physiology; D006801:Humans; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D058990:Molecular Targeted Therapy / Q000379:methods; D050505:Mutant Proteins / Q000494:pharmacology* / Q000627:therapeutic use; D020033:Protein Isoforms / Q000494:pharmacology / Q000627:therapeutic use; D021381:Protein Transport / Q000187:drug effects; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D000068878:Trastuzumab; D014407:Tumor Cells, Cultured
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D050505:Mutant Proteins; D020033:Protein Isoforms; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab