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Oncogene (2016) 35, 61896202 2016 Macmillan Publishers Limited, part of Springer Nature. All rights reserved 0950-9232/16
http://www.nature.com/onc
Web End =www.nature.com/onc
ORIGINAL ARTICLE
MiR-16 mediates trastuzumab and lapatinib response in ErbB-2-positive breast and gastric cancer via its novel targets CCNJ and FUBP1
L Venturutti1, RI Cordo Russo1, MA Rivas2, MF Mercogliano1, F Izzo1, RH Oakley3, MG Pereyra1,4, M De Martino1, CJ Proietti1, P Yankilevich5, JC Roa6,7,8, P Guzmn6, E Cortese9, DH Allemand10, TH Huang11, EH Charreau1, JA Cidlowski3, R Schillaci1 and PV Elizalde1
ErbB-2 amplication/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 benecial. 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 identied 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 ndings 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.
Oncogene (2016) 35, 61896202; doi:http://dx.doi.org/10.1038/onc.2016.151
Web End =10.1038/onc.2016.151 ; published online 9 May 2016
INTRODUCTIONApproximately 1520% of breast cancers (BC) overexpress
ErbB-2, a member of the ErbBs family of receptor tyrosine kinases, which also includes epidermal growth factor receptor/ ErbB-1, ErbB-3 and ErbB-4.1 Until the development of ErbB-2-targeted therapies, ErbB-2-positive subtype was associated with increased metastatic...