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

L. Venturutti, R. I. Cordo Russo, M. A. Rivas, M. F. Mercogliano, F. Izzo, R. H. Oakley, M. G. Pereyra, M. De Martino, C. J. Proietti, P. Yankilevich, J. C. Roa, P. Guzmán, E. Cortese, D. H. Allemand, T. H. Huang, E. H. Charreau, J. A. Cidlowski, R. Schillaci, P. V. Elizalde

Research output: Contribution to journalArticle

32 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)6189-6202
Number of pages14
JournalOncogene
Volume35
Issue number48
DOIs
StatePublished - Dec 1 2016
Externally publishedYes

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ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

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. (2016). MiR-16 mediates trastuzumab and lapatinib response in ErbB-2-positive breast and gastric cancer via its novel targets CCNJ and FUBP1. Oncogene, 35(48), 6189-6202. https://doi.org/10.1038/onc.2016.151