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

• Published in: Oncogene Vol. 35; no. 48; pp. 6189 - 6202
• Main Authors: Venturutti, L, Cordo Russo, R I, Rivas, M A, Mercogliano, M F, Izzo, F, Oakley, R H, Pereyra, M G, De Martino, M, Proietti, C J, Yankilevich, P, Roa, J C, Guzmán, P, Cortese, E, Allemand, D H, Huang, T H, Charreau, E H, Cidlowski, J A, Schillaci, R, Elizalde, P V
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.12.2016; Nature Publishing Group
• Subjects: 1-Phosphatidylinositol 3-kinase; 13/95; 3' Untranslated Regions; 38/39; 38/61; 38/77; 42/109; 631/337/384; 631/67/1347; 631/67/1504; 631/67/395; 64/60; 692/53/2423; 82/80; AKT protein; Animals; Antineoplastic Agents - pharmacology; Apoptosis; Binding Sites; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; c-Myc protein; Cell activation; Cell Biology; Cell Line, Tumor; Cell Proliferation; Cellular signal transduction; Cyclins - genetics; Disease Models, Animal; DNA Helicases - genetics; DNA-Binding Proteins - genetics; Dosage and administration; Drug resistance; Drug Resistance, Neoplasm - genetics; Drug therapy; Enzyme inhibitors; ErbB protein; ErbB-2 protein; Far upstream element-binding protein; Female; Gastric cancer; Gastrointestinal diseases; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; Genes, Tumor Suppressor; Genetic aspects; Genomes; Human Genetics; Humans; Internal Medicine; Lapatinib; Male; Medical innovations; Medicine; Medicine & Public Health; Mice; MicroRNAs - genetics; miRNA; Models, Biological; Monoclonal antibodies; Myc protein; Oncology; original-article; Promoter Regions, Genetic; Protein Kinase Inhibitors - pharmacology; Protein-tyrosine kinase; Proto-Oncogene Proteins c-myc - metabolism; Quinazolines - pharmacology; Receptor, ErbB-2 - antagonists & inhibitors; Receptor, ErbB-2 - metabolism; RNA Interference; RNA-Binding Proteins; Stomach cancer; Stomach Neoplasms - drug therapy; Stomach Neoplasms - genetics; Stomach Neoplasms - metabolism; Trastuzumab; Trastuzumab - pharmacology; Tumor suppressor genes; Tumors
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2016.151

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.