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

Oncogene volume 35, pages 6189–6202 (2016)Cite this article

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A Correction to this article was published on 17 November 2023

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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.

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Acknowledgements

We thank AA Molinolo (UCSD, San Diego, CA, USA) for his constant help. This work was supported by KG090250 investigator-initiated research grant from Susan G Komen for the Cure, Financial Assistance for National Research Projects from the National Institute of Cancer (INC, Argentina), IDB/PICT 2012-668 and PID 2012-066 from National Agency of Scientific Promotion of Argentina (ANPCyT), awarded to PVE; IDB/PICT 2012-382 from ANPCyT, awarded to RS; Oncomed-Reno CONICET 1819/03, from Henry Moore Institute of Argentina, awarded to PVE and RS; IDB/PICT 2008-189 and 2012-1017 from ANPCyT, PIP 59 from CONICET, awarded to CJP.

Author contributions

LV, MAR, RS and PVE were responsible for the conception and design of the study. LV, RICR, MFM, RS and PVE developed methodology. LV, RICR, MAR, MFM, FI, RHO, MGP, MDM, CJP, JCR, PG, EC, DHA, TH-MH, EHC, JAC, RS and PVE acquired the data (and also provided animals, acquired and managed patients, provided facilities, and so on). LV, RICR, MAR, PY, RS and PVE analyzed and interpreted the data. LV and PVE wrote the manuscript. PVE supervised the study. All authors read and approved the final manuscript.

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Authors and Affiliations

  1. Laboratory of Molecular Mechanisms of Carcinogenesis, Instituto de Biología y Medicina Experimental, CONICET, Buenos Aires, Argentina

    L Venturutti, R I Cordo Russo, M F Mercogliano, F Izzo, M G Pereyra, M De Martino, C J Proietti, E H Charreau, R Schillaci & P V Elizalde

  2. Department of Medicine, Weill Cornell Medicine, New York, NY, USA

    M A Rivas

  3. Department of Health and Human Services, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, USA

    R H Oakley & J A Cidlowski

  4. Servicio de Anatomía Patológica, Hospital General de Agudos ‘Juan A Fernández’, Buenos Aires, Argentina

    M G Pereyra

  5. Instituto de Investigación en Biomedicina de Buenos Aires, CONICET—Partner Institute of the Max Planck Society, Buenos Aires, Argentina

    P Yankilevich

  6. Departamento de Anatomía Patológica (BIOREN), Universidad de La Frontera, Temuco, Chile

    J C Roa & P Guzmán

  7. Departamento de Anatomía Patológica, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago de Chile, Chile

    J C Roa

  8. Advanced Center for Chronic Diseases (ACCDIS), Pontificia Universidad Católica de Chile, Santiago de Chile, Santiago, Chile

    J C Roa

  9. Servicio de Ginecología, Hospital Aeronáutico Central, Buenos Aires, Argentina

    E Cortese

  10. Unidad de Patología Mamaria, Hospital General de Agudos 'Juan A Fernández', Buenos Aires, Argentina

    D H Allemand

  11. Department of Molecular Medicine/Institute of Biotechnology, Cancer Therapy and Research Center, University of Texas, San Antonio, TX, USA

    T H Huang

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  1. L Venturutti
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Correspondence to P V Elizalde.

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Venturutti, L., Cordo Russo, R., Rivas, M. et al. MiR-16 mediates trastuzumab and lapatinib response in ErbB-2-positive breast and gastric cancer via its novel targets CCNJ and FUBP1. Oncogene 35, 6189–6202 (2016). https://doi.org/10.1038/onc.2016.151

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