title: MiR-16 mediates trastuzumab and lapatinib response in ErbB-2-positive breast and gastric cancer via its novel targets CCNJ and FUBP1.
abstract: ErbB-2 amplification/overexpression accounts for an aggressive breast cancer (BC) subtype (ErbB-2-positive). Enhanced ErbB-2 expression was also found in gastric cancer (GC) and has been correlated with poor clinical outcome. The ErbB-2-targeted therapies trastuzumab (TZ), a monoclonal antibody, and lapatinib, a tyrosine kinase inhibitor, have proved highly beneficial. However, resistance to such therapies remains a major clinical challenge. We here revealed a novel mechanism underlying the antiproliferative effects of both agents in ErbB-2-positive BC and GC. TZ and lapatinib ability to block extracellular signal-regulated kinases 1/2 and phosphatidylinositol-3 kinase (PI3K)/AKT in sensitive cells inhibits c-Myc activation, which results in upregulation of miR-16. Forced expression of miR-16 inhibited in vitro proliferation in BC and GC cells, both sensitive and resistant to TZ and lapatinib, as well as in a preclinical BC model resistant to these agents. This reveals miR-16 role as tumor suppressor in ErbB-2-positive BC and GC. Using genome-wide expression studies and miRNA target prediction algorithms, we identified cyclin J and far upstream element-binding protein 1 (FUBP1) as novel miR-16 targets, which mediate miR-16 antiproliferative effects. Supporting the clinical relevance of our results, we found that high levels of miR-16 and low or null FUBP1 expression correlate with TZ response in ErbB-2-positive primary BCs. These findings highlight a potential role of miR-16 and FUBP1 as biomarkers of sensitivity to TZ therapy. Furthermore, we revealed miR-16 as an innovative therapeutic agent for TZ- and lapatinib-resistant ErbB-2-positive BC and GC.
authors.affiliation: Laboratory of Molecular Mechanisms of Carcinogenesis, Instituto de Biología y Medicina Experimental, 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, CONICET, Buenos Aires, Argentina.
authors.forename: R I
authors.initials: RI
authors.lastname: Cordo Russo
authors.affiliation: Department of Medicine, Weill Cornell Medicine, New York, NY, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Rivas
authors.affiliation: Laboratory of Molecular Mechanisms of Carcinogenesis, Instituto de Biología y Medicina Experimental, CONICET, Buenos Aires, Argentina.
authors.forename: M F
authors.initials: MF
authors.lastname: Mercogliano
authors.affiliation: Laboratory of Molecular Mechanisms of Carcinogenesis, Instituto de Biología y Medicina Experimental, CONICET, Buenos Aires, Argentina.
authors.forename: F
authors.initials: F
authors.lastname: Izzo
authors.affiliation: Department of Health and Human Services, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, USA.
authors.forename: R H
authors.initials: RH
authors.lastname: Oakley
authors.affiliation: Laboratory of Molecular Mechanisms of Carcinogenesis, Instituto de Biología y Medicina Experimental, CONICET, Buenos Aires, Argentina.|Servicio de Anatomía Patológica, Hospital General de Agudos 'Juan A Fernández', Buenos Aires, Argentina.
authors.forename: M G
authors.initials: MG
authors.lastname: Pereyra
authors.affiliation: Laboratory of Molecular Mechanisms of Carcinogenesis, Instituto de Biología y Medicina Experimental, CONICET, Buenos Aires, Argentina.
authors.forename: M
authors.initials: M
authors.lastname: De Martino
authors.affiliation: Laboratory of Molecular Mechanisms of Carcinogenesis, Instituto de Biología y Medicina Experimental, CONICET, Buenos Aires, Argentina.
authors.forename: C J
authors.initials: CJ
authors.lastname: Proietti
authors.affiliation: Instituto de Investigación en Biomedicina de Buenos Aires, CONICET-Partner Institute of the Max Planck Society, Buenos Aires, Argentina.
authors.forename: P
authors.initials: P
authors.lastname: Yankilevich
authors.affiliation: Departamento de Anatomía Patológica (BIOREN), Universidad de La Frontera, Temuco, Chile.|Departamento de Anatomía Patológica, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago de Chile, Chile.|Advanced Center for Chronic Diseases (ACCDIS), Pontificia Universidad Católica de Chile, Santiago de Chile, Santiago, Chile.
authors.forename: J C
authors.initials: JC
authors.lastname: Roa
authors.affiliation: Departamento de Anatomía Patológica (BIOREN), Universidad de La Frontera, Temuco, Chile.
authors.forename: P
authors.initials: P
authors.lastname: Guzmán
authors.affiliation: Servicio de Ginecología, Hospital Aeronáutico Central, Buenos Aires, Argentina.
authors.forename: E
authors.initials: E
authors.lastname: Cortese
authors.affiliation: Unidad de Patología Mamaria, Hospital General de Agudos 'Juan A Fernández', Buenos Aires, Argentina.
authors.forename: D H
authors.initials: DH
authors.lastname: Allemand
authors.affiliation: Department of Molecular Medicine/Institute of Biotechnology, Cancer Therapy and Research Center, University of Texas, San Antonio, TX, USA.
authors.forename: T H
authors.initials: TH
authors.lastname: Huang
authors.affiliation: Laboratory of Molecular Mechanisms of Carcinogenesis, Instituto de Biología y Medicina Experimental, CONICET, Buenos Aires, Argentina.
authors.forename: E H
authors.initials: EH
authors.lastname: Charreau
authors.affiliation: Department of Health and Human Services, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Cidlowski
authors.affiliation: Laboratory of Molecular Mechanisms of Carcinogenesis, Instituto de Biología y Medicina Experimental, 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, CONICET, Buenos Aires, Argentina.
authors.forename: P V
authors.initials: PV
authors.lastname: Elizalde
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001665:Binding Sites; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016213:Cyclins / Q000235:genetics*; D004265:DNA Helicases / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D016147:Genes, Tumor Suppressor; D006801:Humans; D000077341:Lapatinib; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D008954:Models, Biological; D011401:Promoter Regions, Genetic; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology*; D034622:RNA Interference; D016601:RNA-Binding Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D000068878:Trastuzumab / Q000494:pharmacology*
chemical_list: D020413:3' Untranslated Regions; D000970:Antineoplastic Agents; D016213:Cyclins; D004265:DNA Helicases; D004268:DNA-Binding Proteins; D000077341:Lapatinib; D035683:MicroRNAs; D047428:Protein Kinase Inhibitors; D016271:Proto-Oncogene Proteins c-myc; D011799:Quinazolines; D016601:RNA-Binding Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C000589891:CCNJ protein, human; C492258:FUBP1 protein, human; C505362:MIRN16 microRNA, human