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

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.

Data availability

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

References

  1. 1.

    Garrido-Castro AC, Lin NU, Polyak K. Insights into molecular classifications of triple-negative breast cancer: improving patient selection for treatment. Cancer Discov. 2019;9:176–98.

    CAS  PubMed  PubMed Central  Google Scholar 

  2. 2.

    Schmid P, Adams S, Rugo HS, Schneeweiss A, Barrios CH, Iwata H, et al. Atezolizumab and Nab-paclitaxel in advanced triple-negative breast cancer. N Engl J Med. 2018;379:2108–21.

    CAS  PubMed  Google Scholar 

  3. 3.

    Lehmann BD, Bauer JA, Chen X, Sanders ME, Chakravarthy AB, Shyr Y, et al. Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Investig. 2011;121:2750–67.

    CAS  PubMed  Google Scholar 

  4. 4.

    Prat A, Adamo B, Cheang MC, Anders CK, Carey LA, Perou CM. Molecular characterization of basal-like and non-basal-like triple-negative breast cancer. Oncologist. 2013;18:123–33.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Lehmann BD, Jovanovic B, Chen X, Estrada MV, Johnson KN, Shyr Y, et al. Refinement of triple-negative breast cancer molecular subtypes: implications for neoadjuvant chemotherapy selection. PLoS ONE. 2016;11:e0157368.

    PubMed  PubMed Central  Google Scholar 

  6. 6.

    Burstein MD, Tsimelzon A, Poage GM, Covington KR, Contreras A, Fuqua SA, et al. Comprehensive genomic analysis identifies novel subtypes and targets of triple-negative breast cancer. Clin Cancer Res. 2015;21:1688–98.

    CAS  PubMed  Google Scholar 

  7. 7.

    Prat A, Karginova O, Parker JS, Fan C, He X, Bixby L, et al. Characterization of cell lines derived from breast cancers and normal mammary tissues for the study of the intrinsic molecular subtypes. Breast Cancer Res Treat. 2013;142:237–55.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Perou CM, Sorlie T, Eisen MB, van de RM, Jeffrey SS, Rees CA, et al. Molecular portraits of human breast tumours. Nature. 2000;406:747–52.

    CAS  PubMed  Google Scholar 

  9. 9.

    Slamon DJ, Godolphin W, Jones LA, Holt JA, Wong SG, Keith DE, et al. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science. 1989;244:707–12.

    CAS  PubMed  Google Scholar 

  10. 10.

    Henderson IC, Patek AJ. The relationship between prognostic and predictive factors in the management of breast cancer. Breast Cancer Res Treat. 1998;52:261–88.

    CAS  PubMed  Google Scholar 

  11. 11.

    Ross JS, Slodkowska EA, Symmans WF, Pusztai L, Ravdin PM, Hortobagyi GN. The HER-2 receptor and breast cancer: ten years of targeted anti-HER-2 therapy and personalized medicine. Oncologist. 2009;14:320–68.

    CAS  PubMed  Google Scholar 

  12. 12.

    Li X, Kuang J, Shen Y, Majer MM, Nelson CC, Parsawar K, et al. The atypical histone macroH2A1.2 interacts with HER-2 protein in cancer cells. J Biol Chem. 2012;287:23171–83.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Wang SC, Lien HC, Xia W, Chen IF, Lo HW, Wang Z, et al. Binding at and transactivation of the COX-2 promoter by nuclear tyrosine kinase receptor ErbB-2. Cancer Cell. 2004;6:251–61.

    CAS  PubMed  Google Scholar 

  14. 14.

    Li LY, Chen H, Hsieh YH, Wang YN, Chu HJ, Chen YH, et al. Nuclear ErbB2 enhances translation and cell growth by activating transcription of ribosomal RNA genes. Cancer Res. 2011;71:4269–79.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Kim HP, Yoon YK, Kim JW, Han SW, Hur HS, Park J, et al. Lapatinib, a dual EGFR and HER2 tyrosine kinase inhibitor, downregulates thymidylate synthase by inhibiting the nuclear translocation of EGFR and HER2. PLoS ONE. 2009;4:e5933.

    PubMed  PubMed Central  Google Scholar 

  16. 16.

    Beguelin W, Diaz Flaque MC, Proietti CJ, Cayrol F, Rivas MA, Tkach M, et al. Progesterone receptor induces ErbB-2 nuclear translocation to promote breast cancer growth via a novel transcriptional effect: ErbB-2 function as a coactivator of Stat3. Mol Cell Biol. 2010;30:5456–72.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Cordo Russo RI, Beguelin W, Diaz Flaque MC, Proietti C, Venturutti L, Galigniana NM, et al. Targeting ErbB-2 nuclear localization and function inhibits breast cancer growth and overcomes trastuzumab resistance. Oncogene. 2015;34:3413–28.

    CAS  PubMed  Google Scholar 

  18. 18.

    Diaz Flaque MC, Galigniana NM, Beguelin W, Vicario R, Proietti CJ, Russo RC, et al. Progesterone receptor assembly of a transcriptional complex along with activator protein 1, signal transducer and activator of transcription 3 and ErbB-2 governs breast cancer growth and predicts response to endocrine therapy. Breast Cancer Res. 2013;15:R118.

    PubMed  PubMed Central  Google Scholar 

  19. 19.

    Venturutti L, Romero LV, Urtreger AJ, Chervo MF, Cordo Russo RI, Mercogliano MF, 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. 2016;35:2208–22.

    CAS  PubMed  Google Scholar 

  20. 20.

    Diaz Flaque MC, Vicario R, Proietti CJ, Izzo F, Schillaci R, Elizalde PV. Progestin drives breast cancer growth by inducing p21(CIP1) expression through the assembly of a transcriptional complex among Stat3, progesterone receptor and ErbB-2. Steroids. 2013;78:559–67.

    CAS  PubMed  Google Scholar 

  21. 21.

    Schillaci R, Guzman P, Cayrol F, Beguelin W, Diaz Flaque MC, Proietti CJ, et al. Clinical relevance of ErbB-2/HER2 nuclear expression in breast cancer. Bmc Cancer 2012;12:74.

    PubMed  PubMed Central  Google Scholar 

  22. 22.

    Lee CY, Lin Y, Bratman SV, Feng W, Kuo AH, Scheeren FA, et al. Neuregulin autocrine signaling promotes self-renewal of breast tumor-initiating cells by triggering HER2/HER3 activation. Cancer Res. 2014;74:341–52.

    CAS  PubMed  Google Scholar 

  23. 23.

    Paik S, Kim C, Wolmark N. HER2 status and benefit from adjuvant trastuzumab in breast cancer. N Engl J Med. 2008;358:1409–11.

    CAS  PubMed  Google Scholar 

  24. 24.

    Gautrey H, Jackson C, Dittrich AL, Browell D, Lennard T, Tyson-Capper A. SRSF3 and hnRNP H1 regulate a splicing hotspot of HER2 in breast cancer cells. Rna Biol. 2015;12:1139–51.

    PubMed  PubMed Central  Google Scholar 

  25. 25.

    Brand TM, Iida M, Dunn EF, Luthar N, Kostopoulos KT, Corrigan KL, et al. Nuclear epidermal growth factor receptor is a functional molecular target in triple-negative breast cancer. Mol Cancer Ther. 2014;13:1356–68.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Anido J, Scaltriti M, Bech Serra JJ, Santiago JB, Todo FR, Baselga J, et al. Biosynthesis of tumorigenic HER2 C-terminal fragments by alternative initiation of translation. EMBO J. 2006;25:3234–44.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Pupa SM, Menard S, Morelli D, Pozzi B, De Palo G, Colnaghi MI. The extracellular domain of the c-erbB-2 oncoprotein is released from tumor cells by proteolytic cleavage. Oncogene. 1993;8:2917–23.

    CAS  PubMed  Google Scholar 

  28. 28.

    Lin YZ, Clinton GM. A soluble protein related to the HER-2 proto-oncogene product is released from human breast carcinoma cells. Oncogene 1991;6:639–43.

    CAS  PubMed  Google Scholar 

  29. 29.

    Molina MA, Saez R, Ramsey EE, Garcia-Barchino MJ, Rojo F, Evans AJ, et al. NH(2)-terminal truncated HER-2 protein but not full-length receptor is associated with nodal metastasis in human breast cancer. Clin Cancer Res. 2002;8:347–53.

    CAS  PubMed  Google Scholar 

  30. 30.

    Scaltriti M, Rojo F, Ocana A, Anido J, Guzman M, Cortes J, et al. Expression of p95HER2, a truncated form of the HER2 receptor, and response to anti-HER2 therapies in breast cancer. J Natl Cancer Inst. 2007;99:628–38.

    CAS  PubMed  Google Scholar 

  31. 31.

    Warri AM, Isola JJ, Harkonen PL. Anti-oestrogen stimulation of ERBB2 ectodomain shedding from BT-474 human breast cancer cells with ERBB2 gene amplification. Eur J Cancer. 1996;32A:134–40.

    CAS  PubMed  Google Scholar 

  32. 32.

    Ferreira IG, Pucci M, Venturi G, Malagolini N, Chiricolo M, Dall’Olio F. Glycosylation as a main regulator of growth and death factor receptors signaling. Int J Mol Sci. 2018;19:

  33. 33.

    Watanabe M, Terasawa K, Kaneshiro K, Uchimura H, Yamamoto R, Fukuyama Y, et al. Improvement of mass spectrometry analysis of glycoproteins by MALDI-MS using 3-aminoquinoline/alpha-cyano-4-hydroxycinnamic acid. Anal Bioanal Chem. 2013;405:4289–93.

    CAS  PubMed  Google Scholar 

  34. 34.

    Frei AP, Jeon OY, Kilcher S, Moest H, Henning LM, Jost C, et al. Direct identification of ligand-receptor interactions on living cells and tissues. Nat Biotechnol. 2012;30:997–1001.

    CAS  PubMed  Google Scholar 

  35. 35.

    Contessa JN, Bhojani MS, Freeze HH, Rehemtulla A, Lawrence TS. Inhibition of N-linked glycosylation disrupts receptor tyrosine kinase signaling in tumor cells. Cancer Res. 2008;68:3803–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Duarte HO, Balmana M, Mereiter S, Osorio H, Gomes J, Reis CA. Gastric cancer cell glycosylation as a modulator of the ErbB2 oncogenic receptor. Int J Mol Sci. 2017;18:

  37. 37.

    Holbro T, Beerli RR, Maurer F, Koziczak M, Barbas CF III, Hynes NE. The ErbB2/ErbB3 heterodimer functions as an oncogenic unit: ErbB2 requires ErbB3 to drive breast tumor cell proliferation. Proc Natl Acad Sci USA. 2003;100:8933–8.

    CAS  PubMed  Google Scholar 

  38. 38.

    Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol. 2001;2:127–37.

    CAS  PubMed  Google Scholar 

  39. 39.

    Pal S, Gupta R, Kim H, Wickramasinghe P, Baubet V, Showe LC, et al. Alternative transcription exceeds alternative splicing in generating the transcriptome diversity of cerebellar development. Genome Res. 2011;21:1260–72.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Turpin J, Ling C, Crosby EJ, Hartman ZC, Simond AM, Chodosh LA, et al. The ErbB2DeltaEx16 splice variant is a major oncogenic driver in breast cancer that promotes a pro-metastatic tumor microenvironment. Oncogene. 2016;35:6053–64.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Kwong KY, Hung MC. A novel splice variant of HER2 with increased transformation activity. Mol Carcinog. 1998;23:62–68.

    CAS  PubMed  Google Scholar 

  42. 42.

    Castiglioni F, Tagliabue E, Campiglio M, Pupa SM, Balsari A, Menard S. Role of exon-16-deleted HER2 in breast carcinomas. Endocr Relat Cancer. 2006;13:221–32.

    CAS  PubMed  Google Scholar 

  43. 43.

    Mitra D, Brumlik MJ, Okamgba SU, Zhu Y, Duplessis TT, Parvani JG, et al. An oncogenic isoform of HER2 associated with locally disseminated breast cancer and trastuzumab resistance. Mol Cancer Ther. 2009;8:2152–62.

    CAS  PubMed  Google Scholar 

  44. 44.

    Alajati A, Sausgruber N, Aceto N, Duss S, Sarret S, Voshol H, et al. Mammary tumor formation and metastasis evoked by a HER2 splice variant. Cancer Res. 2013;73:5320–7.

    CAS  PubMed  Google Scholar 

  45. 45.

    Giri DK, Ali-Seyed M, Li LY, Lee DF, Ling P, Bartholomeusz G, et al. Endosomal transport of ErbB-2: mechanism for nuclear entry of the cell surface receptor. Mol Cell Biol. 2005;25:11005–18.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46.

    Thiel KW, Carpenter G. Epidermal growth factor receptor juxtamembrane region regulates allosteric tyrosine kinase activation. Proc Natl Acad Sci USA. 2007;104:19238–43.

    CAS  PubMed  Google Scholar 

  47. 47.

    Zhang X, Gureasko J, Shen K, Cole PA, Kuriyan J. An allosteric mechanism for activation of the kinase domain of epidermal growth factor receptor. Cell. 2006;125:1137–49.

    CAS  PubMed  Google Scholar 

  48. 48.

    Red Brewer M, Choi SH, Alvarado D, Moravcevic K, Pozzi A, Lemmon MA, et al. The juxtamembrane region of the EGF receptor functions as an activation domain. Mol Cell. 2009;34:641–51.

    PubMed  Google Scholar 

  49. 49.

    Jura N, Endres NF, Engel K, Deindl S, Das R, Lamers MH, et al. Mechanism for activation of the EGF receptor catalytic domain by the juxtamembrane segment. Cell. 2009;137:1293–307.

    PubMed  PubMed Central  Google Scholar 

  50. 50.

    Linggi B, Cheng QC, Rao AR, Carpenter G. The ErbB-4 s80 intracellular domain is a constitutively active tyrosine kinase. Oncogene. 2006;25:160–3.

    CAS  PubMed  Google Scholar 

  51. 51.

    Wood ER, Shewchuk LM, Ellis B, Brignola P, Brashear RL, Caferro TR, et al. 6-Ethynylthieno[3,2-d]- and 6-ethynylthieno[2,3-d]pyrimidin-4-anilines as tunable covalent modifiers of ErbB kinases. Proc Natl Acad Sci USA. 2008;105:2773–8.

    CAS  PubMed  Google Scholar 

  52. 52.

    Jura N, Zhang X, Endres NF, Seeliger MA, Schindler T, Kuriyan J. Catalytic control in the EGF receptor and its connection to general kinase regulatory mechanisms. Mol Cell. 2011;42:9–22.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 53.

    Elizalde PV, Cordo Russo RI, Chervo MF, Schillaci R. ErbB-2 nuclear function in breast cancer growth, metastasis and resistance to therapy. Endocr Relat Cancer. 2016;23:T243–T257.

    CAS  PubMed  Google Scholar 

  54. 54.

    Hsu YH, Yao J, Chan LC, Wu TJ, Hsu JL, Fang YF, et al. Definition of PKC-alpha, CDK6, and MET as therapeutic targets in triple-negative breast cancer. Cancer Res. 2014;74:4822–35.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55.

    Al Ejeh F, Miranda M, Shi W, Simpson PT, Song S, Vargas AC, et al. Kinome profiling reveals breast cancer heterogeneity and identifies targeted therapeutic opportunities for triple negative breast cancer. Oncotarget. 2014;5:3145–58.

    PubMed  PubMed Central  Google Scholar 

  56. 56.

    Ortiz-Ruiz MJ, Alvarez-Fernandez S, Parrott T, Zaknoen S, Burrows FJ, Ocana A, et al. Therapeutic potential of ERK5 targeting in triple negative breast cancer. Oncotarget. 2014;5:11308–18.

    PubMed  PubMed Central  Google Scholar 

  57. 57.

    Yunokawa M, Koizumi F, Kitamura Y, Katanasaka Y, Okamoto N, Kodaira M, et al. Efficacy of everolimus, a novel mTOR inhibitor, against basal-like triple-negative breast cancer cells. Cancer Sci. 2012;103:1665–71.

    CAS  PubMed  Google Scholar 

  58. 58.

    Daemen A, Manning G. HER2 is not a cancer subtype but rather a pan-cancer event and is highly enriched in AR-driven breast tumors. Breast Cancer Res. 2018;20:8.

    PubMed  PubMed Central  Google Scholar 

  59. 59.

    Le DuF, Eckhardt BL, Lim B, Litton JK, Moulder S, Meric-Bernstam F, et al. Is the future of personalized therapy in triple-negative breast cancer based on molecular subtype? Oncotarget. 2015;6:12890–908.

    Google Scholar 

  60. 60.

    Grigoriadis A, Mackay A, Noel E, Wu PJ, Natrajan R, Frankum J, et al. Molecular characterisation of cell line models for triple-negative breast cancers. BMC Genomics. 2012;13:619.

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61.

    Sasso M, Bianchi F, Ciravolo V, Tagliabue E, Campiglio M. HER2 splice variants and their relevance in breast cancer. J Nucleic Acids Investig. 2011;2(e9):52–58.

    CAS  Google Scholar 

  62. 62.

    Siegel PM, Ryan ED, Cardiff RD, Muller WJ. Elevated expression of activated forms of Neu/ErbB-2 and ErbB-3 are involved in the induction of mammary tumors in transgenic mice: implications for human breast cancer. EMBO J. 1999;18:2149–64.

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63.

    Castagnoli L, Ghedini GC, Koschorke A, Triulzi T, Dugo M, Gasparini P, et al. Pathobiological implications of the d16HER2 splice variant for stemness and aggressiveness of HER2-positive breast cancer. Oncogene. 2017;36:1721–32.

    CAS  PubMed  Google Scholar 

  64. 64.

    Tilio M, Gambini V, Wang J, Garulli C, Kalogris C, Andreani C, et al. Irreversible inhibition of Delta16HER2 is necessary to suppress Delta16HER2-positive breast carcinomas resistant to Lapatinib. Cancer Lett. 2016;381:76–84.

    CAS  PubMed  Google Scholar 

  65. 65.

    Menon R, Im H, Zhang EY, Wu SL, Chen R, Snyder M, et al. Distinct splice variants and pathway enrichment in the cell-line models of aggressive human breast cancer subtypes. J Proteome Res. 2014;13:212–27.

    CAS  PubMed  Google Scholar 

  66. 66.

    Reyes A, Huber W. Alternative start and termination sites of transcription drive most transcript isoform differences across human tissues. Nucleic Acids Res. 2018;46:582–92.

    CAS  PubMed  Google Scholar 

  67. 67.

    Kelemen O, Convertini P, Zhang Z, Wen Y, Shen M, Falaleeva M, et al. Function of alternative splicing. Gene. 2013;514:1–30.

    CAS  PubMed  Google Scholar 

  68. 68.

    Proietti CJ, Rosemblit C, Beguelin W, Rivas MA, Diaz Flaque MC, Charreau EH, et al. Activation of Stat3 by heregulin/ErbB-2 through the co-option of progesterone receptor signaling drives breast cancer growth. Mol Cell Biol. 2009;29:1249–65.

    CAS  PubMed  Google Scholar 

  69. 69.

    Ito K, Park SH, Nayak A, Byerly JH, Irie HY. PTK6 Inhibition Suppresses Metastases of Triple-Negative Breast Cancer via SNAIL-Dependent E-Cadherin Regulation. Cancer Res. 2016;76:4406–17.

    CAS  PubMed  Google Scholar 

  70. 70.

    Tryndyak VP, Beland FA, Pogribny IP. E-cadherin transcriptional down-regulation by epigenetic and microRNA-200 family alterations is related to mesenchymal and drug-resistant phenotypes in human breast cancer cells. Int J Cancer. 2010;126:2575–83.

    CAS  PubMed  Google Scholar 

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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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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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