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Artículo

MiR-16 mediates trastuzumab and lapatinib response in ErbB-2-positive breast and gastric cancer via its novel targets CCNJ and FUBP1

Venturutti, LeandroIcon ; Cordo Russo, Rosalia InesIcon ; Rivas, Martin AlfredoIcon ; Mercogliano, María FlorenciaIcon ; Izzo, FrancoIcon ; Oakley, R. H.; Pereyra, M. G.; De Martino, M.; Proietti Anastasi, Cecilia JazmínIcon ; Yankilevich, PatricioIcon ; Roa, J. C.; Guzmán, P.; Cortese, E.; Allemandi, Daniel AlbertoIcon ; Huang, T. H.; Charreau, Eduardo HernanIcon ; Cidlowski, J. A.; Schillaci, RoxanaIcon ; Elizalde, Patricia VirginiaIcon
Fecha de publicación: 03/2016
Editorial: Nature Publishing Group
Revista: Oncogene
ISSN: 0950-9232
e-ISSN: 1476-5594
Idioma: Inglés
Tipo de recurso: Artículo publicado
Clasificación temática:
Bioquímica y Biología Molecular; Patología

Resumen

ErbB-2 amplification/overexpression accounts for an aggressive breast cancer (BC) subtype (ErbB-2-positive). Enhanced ErbB-2expression was also found in gastric cancer (GC) and has been correlated with poor clinical outcome. The ErbB-2-targeted therapiestrastuzumab (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 theantiproliferative effects of both agents in ErbB-2-positive BC and GC. TZ and lapatinib ability to block extracellular signal-regulatedkinases 1/2 and phosphatidylinositol-3 kinase (PI3K)/AKT in sensitive cells inhibits c-Myc activation, which results in upregulation ofmiR-16. Forced expression of miR-16 inhibited in vitro proliferation in BC and GC cells, both sensitive and resistant to TZ andlapatinib, 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 farupstream element-binding protein 1 (FUBP1) as novel miR-16 targets, which mediate miR-16 antiproliferative effects. Supportingthe clinical relevance of our results, we found that high levels of miR-16 and low or null FUBP1 expression correlate with TZresponse in ErbB-2-positive primary BCs. These findings highlight a potential role of miR-16 and FUBP1 as biomarkers of sensitivityto TZ therapy. Furthermore, we revealed miR-16 as an innovative therapeutic agent for TZ- and lapatinib-resistant ErbB-2-positiveBC and GC.
Palabras clave: Mir-16 , Breast Cancer , Trastuzumab Resistance
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info:eu-repo/semantics/openAccess Excepto donde se diga explícitamente, este item se publica bajo la siguiente descripción: Creative Commons Attribution-NonCommercial-ShareAlike 2.5 Unported (CC BY-NC-SA 2.5)
Identificadores
URI: http://hdl.handle.net/11336/23585
URL: http://www.nature.com/onc/journal/v35/n48/full/onc2016151a.html?foxtrotcallback=
DOI: http://dx.doi.org/10.1038/onc.2016.151
URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5832962/
Colecciones
Articulos(IBIOBA - MPSP)
Articulos de INST. D/INV.EN BIOMED.DE BS AS-CONICET-INST. PARTNER SOCIEDAD MAX PLANCK
Articulos(IBYME)
Articulos de INST.DE BIOLOGIA Y MEDICINA EXPERIMENTAL (I)
Citación
Venturutti, Leandro; Cordo Russo, Rosalia Ines; Rivas, Martin Alfredo; Mercogliano, María Florencia; Izzo, Franco; et al.; MiR-16 mediates trastuzumab and lapatinib response in ErbB-2-positive breast and gastric cancer via its novel targets CCNJ and FUBP1; Nature Publishing Group; Oncogene; 35; 48; 3-2016; :6189-6202
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