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

VENTURUTTI, LEANDRO; CORDO RUSSO, ROSALÍA; RIVAS, MARTÍN A.; MERCOGLIANO, MARÍA FLORENCIA; IZZO, FRANCO; OAKLEY, ROBERT H; PEREYRA, MATÍAS; DE MARTINO, MARA; PROIETTI, CECILIA J.; YANKILEVICH, PATRICIO; ROA, JUAN CARLOS; GUZMÁN, PABLO; CORTESE, EDUARDO; ALLEMAND, DANIEL; HUANG, TIM; CIDLOWSKI, JOHN; SCHILLACI, ROXANA; ELIZALDE, PATRICIA V.

ONCOGENE

NATURE PUBLISHING GROUP

Lugar: Londres; Año: 2016

0950-9232

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.Oncogene advance online publication, 9 May 2016; doi:10.1038/onc.2016.151.