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

Oncogene. 2016 Dec 1;35(48):6189-6202. doi: 10.1038/onc.2016.151. Epub 2016 May 9.


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.

MeSH terms

  • 3' Untranslated Regions
  • Animals
  • Antineoplastic Agents / pharmacology
  • Binding Sites
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / metabolism
  • Cell Line, Tumor
  • Cell Proliferation
  • Cyclins / genetics*
  • DNA Helicases / genetics*
  • DNA-Binding Proteins / genetics*
  • Disease Models, Animal
  • Drug Resistance, Neoplasm / genetics
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Genes, Tumor Suppressor
  • Humans
  • Lapatinib
  • Male
  • Mice
  • MicroRNAs / genetics*
  • Models, Biological
  • Promoter Regions, Genetic
  • Protein Kinase Inhibitors / pharmacology
  • Proto-Oncogene Proteins c-myc / metabolism
  • Quinazolines / pharmacology*
  • RNA Interference
  • RNA-Binding Proteins
  • Receptor, ErbB-2 / antagonists & inhibitors
  • Receptor, ErbB-2 / metabolism
  • Stomach Neoplasms / drug therapy
  • Stomach Neoplasms / genetics*
  • Stomach Neoplasms / metabolism
  • Trastuzumab / pharmacology*


  • 3' Untranslated Regions
  • Antineoplastic Agents
  • CCNJ protein, human
  • Cyclins
  • DNA-Binding Proteins
  • FUBP1 protein, human
  • MIRN16 microRNA, human
  • MicroRNAs
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins c-myc
  • Quinazolines
  • RNA-Binding Proteins
  • Lapatinib
  • Receptor, ErbB-2
  • DNA Helicases
  • Trastuzumab