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

VENTURUTTI L; CORDO RUSSO R; RIVAS MA; MERCOGLIANO MF; IZZO F; OAKLEY RH; PEREYRA MG; DE MARTINO M; PROIETTI CJ; YANKILEVICH P; ROA JC; GUZMÁN P; CORTESE E; ALLEMAND D; HUANG T H-M; CHARREAU EH; CIDLOWSKI JA; SCHILLACI R; ELIZALDE PV

ONCOGENE

NATURE PUBLISHING GROUP

Lugar: Londres; Año: 2016 vol. 35 p. 6189 - 6202

0950-9232

ErbB-2 amplification/overexpression accounts for an aggressive breast cancer (BC) subtype (ErbB-2 positive). Enhanced ErbB-2expression was also found in gastric cancer (GC) and has been correlated with poor clinical outcome. The ErbB-2-targeted therapiestrastuzumab (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 theQ2 antiproliferative effects of both agents in ErbB-2-positive BC and GC. TZ and lapatinib ability to block Erk1/2 andphosphatidylinositol-3 kinase (PI3K)/AKT in sensitive cells inhibits c-Myc activation, which results in upregulation of miR-16. Forcedexpression of miR-16 inhibited in vitro proliferation in BC and GC cells, both sensitive and resistant to TZ and lapatinib, as well as ina preclinical BC model resistant to these agents. This reveals miR-16 role as tumor suppressor in ErbB-2-positive BC and GC. Usinggenome-wide expression studies and miRNA target prediction algorithms, we identified cyclin J and far upstream element-bindingprotein 1 as novel miR-16 targets, which mediate miR-16 antiproliferative effects. Supporting the clinical relevance of our results, wefound that high levels of miR-16 and low or null FUBP1 expression correlate with TZ response in ErbB-2-positive primary BCs. Thesefindings highlight a potential role of miR-16 and FUBP1 as biomarkers of sensitivity to TZ therapy. Furthermore, we revealed miR-16as an innovative therapeutic agent for TZ- and lapatinib-resistant ErbB-2-positive BC and GC.