Journal
ONCOGENE
Volume 35, Issue 48, Pages 6189-6202Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2016.151
Keywords
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Funding
- Susan G Komen for the Cure [KG090250]
- National Institute of Cancer (INC, Argentina)
- National Agency of Scientific Promotion of Argentina (ANPCyT) [IDB/PICT 2012-668, PID 2012-066]
- ANPCyT [IDB/PICT 2012-382, IDB/PICT 2008-189, 2012-1017]
- Henry Moore Institute of Argentina [Oncomed-Reno CONICET 1819/03]
- CONICET [PIP 59]
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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-2positive 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.
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