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  • Original Article
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Stat3 regulates ErbB-2 expression and co-opts ErbB-2 nuclear function to induce miR-21 expression, PDCD4 downregulation and breast cancer metastasis

Oncogene volume 35, pages 2208–2222 (2016)Cite this article

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A Correction to this article was published on 14 February 2024

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Abstract

Membrane overexpression of the receptor tyrosine kinase ErbB-2 (MErbB-2) accounts for a clinically aggressive breast cancer (BC) subtype (ErbB-2-positive) with increased incidence of metastases. We and others demonstrated that nuclear ErbB-2 (NErbB-2) also plays a key role in BC and is a poor prognostic factor in ErbB-2-positive tumors. The signal transducer and activator of transcription 3 (Stat3), another player in BC, has been recognized as a downstream mediator of MErbB-2 action in BC metastasis. Here, we revealed an unanticipated novel direction of the ErbB-2 and Stat3 interaction underlying BC metastasis. We found that Stat3 binds to its response elements (GAS) at the ErbB-2 promoter to upregulate ErbB-2 transcription in metastatic, ErbB-2-positive BC. We validated these results in several BC subtypes displaying metastatic and non-metastatic ability, highlighting Stat3 general role as upstream regulator of ErbB-2 expression in BC. Moreover, we showed that Stat3 co-opts NErbB-2 function by recruiting ErbB-2 as its coactivator at the GAS sites in the promoter of microRNA-21 (miR-21), a metastasis-promoting microRNA (miRNA). Using an ErbB-2 nuclear localization domain mutant and a constitutively activated ErbB-2 variant, we found that NErbB-2 role as a Stat3 coactivator and also its direct role as transcription factor upregulate miR-21 in BC. This reveals a novel function of NErbB-2 as a regulator of miRNAs expression. Increased levels of miR-21, in turn, downregulate the expression of the metastasis-suppressor protein programmed cell death 4 (PDCD4), a validated miR-21 target. Using an in vivo model of metastatic ErbB-2-postive BC, in which we silenced Stat3 and reconstituted ErbB-2 or miR-21 expression, we showed that both are downstream mediators of Stat3-driven metastasis. Supporting the clinical relevance of our results, we found an inverse correlation between ErbB-2/Stat3 nuclear co-expression and PDCD4 expression in ErbB-2-positive primary invasive BCs. Our findings identify Stat3 and NErbB-2 as novel therapeutic targets to inhibit ErbB-2-positive BC metastasis.

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Acknowledgements

We thank MC Hung (MD Anderson Cancer Center, Houston, TX, USA) for his generous gift of the hErbB-2ΔNLS, which indeed made this work possible, AA Molinolo (NIH, Bethesda, MD, USA) for his constant help and support and V Chiauzzi for her technical assistance. This work was supported by the Susan G Komen for the Cure KG090250 investigator-initiated research Grant, and 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 2012-0382 (awarded to RS) and Oncomed-Reno CONICET 1819/03, from the Henry Moore Institute of Argentina (awarded to PVE and RS).

Author contributions

PVE, LV and RS were responsible for the conception and design of the study. PVE, LV, LR, AJU, MFC, RICR, VS, EBKJ and RS developed methodology. PVE, LV, LR, AJU, MFC, RICR, MFM, GI, MGP, CJP, FI, MCDF, VS, JCR, PG, EBKJ, EHC and RS acquired the data (and also provided animals, acquired and managed patients, provided facilities and so on). PVE, LV, LR, AJU and RS analyzed and interpreted the data. PVE, LV and RS 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, L V Romero, M F Chervo, R I Cordo Russo, M F Mercogliano, M G Pereyra, C J Proietti, F Izzo, M C Díaz Flaqué, V Sundblad, E H Charreau, R Schillaci & P V Elizalde

  2. Research Area, Institute of Oncology ‘Angel H. Roffo’, University of Buenos Aires, Buenos Aires, Argentina

    A J Urtreger & E D Bal de Kier Joffé

  3. Servicio de Patología, Sanatorio Mater Dei, Buenos Aires, Argentina

    G Inurrigarro

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

    J C Roa & P Guzmán

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

    J C Roa

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

    J C Roa

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  1. L Venturutti
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Correspondence to R Schillaci or P V Elizalde.

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Venturutti, L., Romero, L., Urtreger, A. et al. Stat3 regulates ErbB-2 expression and co-opts ErbB-2 nuclear function to induce miR-21 expression, PDCD4 downregulation and breast cancer metastasis. Oncogene 35, 2208–2222 (2016). https://doi.org/10.1038/onc.2015.281

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  • DOI: https://doi.org/10.1038/onc.2015.281

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