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Targeting ErbB-2 nuclear localization and function inhibits breast cancer growth and overcomes trastuzumab resistance

Oncogene volume 34, pages 3413–3428 (2015)Cite this article

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A Correction to this article was published on 08 September 2023

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Abstract

Membrane overexpression of ErbB-2/HER2 receptor tyrosine kinase (membrane ErbB-2 (MErbB-2)) has a critical role in breast cancer (BC). We and others have also shown the role of nuclear ErbB-2 (NErbB-2) in BC, whose presence we identified as a poor prognostic factor in MErbB-2-positive tumors. Current anti-ErbB-2 therapies, as with the antibody trastuzumab (Ttzm), target only MErbB-2. Here, we found that blockade of NErbB-2 action abrogates growth of BC cells, sensitive and resistant to Ttzm, in a scenario in which ErbB-2, ErbB-3 and Akt are phosphorylated, and ErbB-2/ErbB-3 dimers are formed. Also, inhibition of NErbB-2 presence suppresses growth of a preclinical BC model resistant to Ttzm. We showed that at the cyclin D1 promoter, ErbB-2 assembles a transcriptional complex with Stat3 (signal transducer and activator of transcription 3) and ErbB-3, another member of the ErbB family, which reveals the first nuclear function of ErbB-2/ErbB-3 dimer. We identified NErbB-2 as the major proliferation driver in Ttzm-resistant BC, and demonstrated that Ttzm inability to disrupt the Stat3/ErbB-2/ErbB-3 complex underlies its failure to inhibit growth. Furthermore, our results in the clinic revealed that nuclear interaction between ErbB-2 and Stat3 correlates with poor overall survival in primary breast tumors. Our findings challenge the paradigm of anti-ErbB-2 drug design and highlight NErbB-2 as a novel target to overcome Ttzm resistance.

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Acknowledgements

We thank Mien-Chie Hung (MD Anderson Cancer Center, Houston, TX, USA) for his generous gift of the hErbB-2ΔNLS, which indeed made this work possible, and AA Molinolo (NIH, Bethesda, MD, USA) for his constant help and support. We also thank J Giudice (Baylor College of Medicine, Houston, TX, USA) for help with quantification of confocal images, and V Chiauzzi for her excellent technical assistance. This work was supported by the Susan G Komen for the Cure KG090250 investigator-initiated research Grant, IDB/PICT 2012-668 and PID 2012-066 from the National Agency of Scientific Promotion of Argentina (all of them awarded to PVE), IDB/PICT 2012-382 from the National Agency of Scientific Promotion of Argentina (awarded to RS) and Oncomed-Reno CONICET 1819/03, from the Henry Moore Institute of Argentina (awarded to PVE and RS).

Author Contributions

PVE, RICR and WB were responsible for the conception and design of the study. RICR and WB contributed equally to this work. PVE, WB, RICR, MCDF, CJP, PG and RS developed methodology. RICR, WB, PVE, MCDF, CJP, LV, NG, MT, PG, NAO, JCR, RS and EHC acquired the data (and also provided animals, acquired and managed patients, provided facilities, etc.). PVE, RICR, WB, RS, PG and JCR analyzed and interpreted the data. PVE wrote the manuscript with assistance from RICR. PVE supervised the study. All authors read and approved the final manuscript.

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  1. R I Cordo Russo and W Béguelin: These authors contributed equally to this work.

Authors and Affiliations

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

    R I Cordo Russo, W Béguelin, M C Díaz Flaqué, C J Proietti, L Venturutti, N Galigniana, M Tkach, E H Charreau, R Schillaci & P V Elizalde

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

    P Guzmán & J C Roa

  3. Department of Medicine, Division of Hematology/Oncology, Geffen School of Medicine at UCLA, Los Angeles, CA, USA

    N A O'Brien

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Cordo Russo, R., Béguelin, W., Díaz Flaqué, M. et al. Targeting ErbB-2 nuclear localization and function inhibits breast cancer growth and overcomes trastuzumab resistance. Oncogene 34, 3413–3428 (2015). https://doi.org/10.1038/onc.2014.272

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