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Canonical ErbB-2 isoform and ErbB-2 variant c located in the nucleus drive triple negative breast cancer growth

Oncogene volume 39, pages 6245–6262 (2020)Cite this article

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Abstract

Triple negative breast cancer (TNBC) refers to tumors that do not express clinically significant levels of estrogen and progesterone receptors, and lack membrane overexpression or gene amplification of ErbB-2/HER2, a receptor tyrosine kinase. Transcriptome and proteome heterogeneity of TNBC poses a major challenge to precision medicine. Clinical biomarkers and targeted therapies for this disease remain elusive, so chemotherapy has been the standard of care for early and metastatic TNBC. Our present findings placed ErbB-2 in an unanticipated scenario: the nucleus of TNBC (NErbB-2). Our study on ErbB-2 alternative splicing events, using a PCR-sequencing approach combined with an RNA interference strategy, revealed that TNBC cells express either the canonical (wild-type) ErbB-2, encoded by transcript variant 1, or the non-canonical ErbB-2 isoform c, encoded by alternative variant 3 (RefSeq), or both. These ErbB-2 isoforms function in the nucleus as transcription factors. Evicting both from the nucleus or silencing isoform c only, blocks TN cell and tumor growth. This reveals not only NErbB-2 canonical and alternative isoforms role as targets of therapy in TNBC, but also isoform c dominant oncogenic potential. Furthermore, we validated our findings in the clinic and observed that NErbB-2 correlates with poor prognosis in primary TN tumors, disclosing NErbB-2 as a novel biomarker for TNBC. Our discoveries challenge the present scenario of drug development for personalized BC medicine that focuses on wild-type RefSeq proteins, which conserve the canonical domains and are located in their classical cellular compartments.

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Fig. 1: NErbB-2 is expressed and shows clinical relevance in TNBC.
Fig. 2: Expression of ErbB-2 transcript variants in TNBC.
Fig. 3: siRNAs targeting the common coding region of transcript variants 1–4, and ErbB-2Δ16 are unable to silence p165ErbB-2 expression.
Fig. 4: Nuclear ErbB-2 isoform c induces proliferation of TNBC of the basal and mesenchymal subtypes.
Fig. 5: Blockade of ErbB-2 nuclear presence inhibits TNBC growth.
Fig. 6: NErbB-2 function as TF induces Erk5 expression in TNBC to promote growth.
Fig. 7: Model of nuclear ErbB-2 action governing TNBC growth.

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All data generated or analyzed during this study are included in this article (and its Supplementary information files).

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Acknowledgements

In memory of EH Charreau, our colleague and dear friend. We thank A Molinolo (UCSD, USA) and E Gil Deza (Instituto Oncológico Henry Moore, Argentina) for their advice. This work was supported by IDB/PICT 2012-668, PID 2012-066, PICT 2015-1587, PICT 2017-1072 from the National Agency of Scientific Promotion of Argentina, INC 2016 research grant from Nat. Cancer Institute of Argentina, and Fondation Nelia et Amadeo Barletta Research Grant, all awarded to PVE, and Foundation Alberto J. Roemmers Research Grant awarded to PVE and RICR.

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  1. Deceased author: José L. Daniotti

Authors and Affiliations

  1. Laboratory of Molecular Mechanisms of Carcinogenesis and Molecular Endocrinology, Instituto de Biología y Medicina Experimental (IBYME), CONICET, Vuelta de Obligado 2490, C1428ADN, Buenos Aires, Argentina

    María F. Chervo, Rosalía I. Cordo Russo, Franco Izzo, Mara De Martino, Mauro E. Cenciarini, Violeta A. Chiauzzi, Lucía Santa María de la Parra, Matías G. Pereyra, Cecilia J. Proietti, Roxana Schillaci & Patricia V. Elizalde

  2. Universidad de Buenos Aires (UBA), Facultad de Ciencias Exactas y Naturales, Departamento de Fisiología, Biología Molecular y Celular and CONICET-UBA, Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE), C1428EHA, Buenos Aires, Argentina

    Ezequiel Petrillo

  3. Laboratorio de Microbiología Aplicada, Biotecnología y Bioinformática de Levaduras, Instituto Andino-Patagónico de Tecnologías Biológicas y Geoambientales (IPATEC), CONICET-UNComahue, Quintral 1250, 8400, Bariloche, Argentina

    Nicolás Bellora

  4. Laboratory of Molecular and Cellular Therapy, Leloir Institute-CONICET, Av Patricias Argentinas 435, C1405BWE, Buenos Aires, Argentina

    Leandro N. Güttlein & Osvaldo L. Podhajcer

  5. Centro de Investigaciones en Química Biológica de Córdoba, CIQUIBIC, CONICET and Departamento de Química Biológica Ranwel Caputto, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Ciudad Universitaria, X5000HUA, Córdoba, Argentina

    José L. Daniotti

  6. Unidad de Patología Mamaria, Hospital General de Agudos Juan A. Fernández, C1425AGP, Buenos Aires, Argentina

    Agustina Dupont, Sabrina Barchuk, Silvina Figurelli & Daniel Lopez Della Vecchia

  7. Departamento de Anatomía Patológica (BIOREN), Universidad de La Frontera, Temuco, Casilla 54-D, Chile

    Juan C. Roa & Pablo Guzmán

  8. Department of Pathology, School of Medicine, Pontificia Universidad Católica de Chile, 8330024, Santiago de Chile, Chile

    Juan C. Roa

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

    Juan C. Roa

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  1. María F. Chervo
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Contributions

Conceptualization, PVE, MFC, RICR, and EP; Methodology, MFC, RICR, FI, MDM, MEC, VAC, LSMDLP, MGP, LNG, AD, CJP, and PVE; Resources, OLP, JLD, SB, SF, DLDV, JCR, PG, and PVE; Formal Analysis, MFC, RICR, NB, MGP, PG, RS, and PVE; Writing, PVE, MFC, and RICR with input of EP; Supervision, Project administration, and Funding acquisition, PVE.

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Correspondence to Patricia V. Elizalde.

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Chervo, M.F., Cordo Russo, R.I., Petrillo, E. et al. Canonical ErbB-2 isoform and ErbB-2 variant c located in the nucleus drive triple negative breast cancer growth. Oncogene 39, 6245–6262 (2020). https://doi.org/10.1038/s41388-020-01430-9

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