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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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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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