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Nuclear ErbB-2: a Novel Therapeutic Target in ErbB-2-Positive Breast Cancer?

  • Rosalía I. Cordo RussoEmail author
  • María F. Chervo
  • Santiago Madera
  • Eduardo H. Charreau
  • Patricia V. ElizaldeEmail author
Review
  • 47 Downloads

Abstract

Membrane overexpression of ErbB-2 (MErbB-2), a member of the ErbB family of receptor tyrosine kinases, occurs in 15–20% of breast cancers (BC) and constitutes a therapeutic target in this BC subtype (ErbB-2-positive). Although MErbB-2-targeted therapies have significantly improved patients’ clinical outcome, resistance to available drugs is still a major issue in the clinic. Lack of accurate biomarkers for predicting responses to anti-ErbB-2 drugs at the time of diagnosis is also an important unresolved issue. Hence, a better understanding of the ErbB-2 signaling pathway constitutes a critical task in the battle against BC. In its canonical mechanism of action, MErbB-2 activates downstream signaling pathways, which transduce its proliferative effects in BC. The dogma of ErbB-2 mechanism of action has been challenged by the demonstration that MErbB-2 migrates to the nucleus, where it acts as a transcriptional regulator. Accumulating findings demonstrate that nuclear ErbB-2 (NErbB-2) is involved in BC growth and metastasis. Emerging evidence also reveal a role of NErbB-2 in the response to available anti-MErbB-2 agents. Here, we will review NErbB-2 function in BC and will particularly discuss the role of NErbB-2 as a novel target for therapy in ErbB-2-positive BC.

Keywords

Nuclear ErbB-2 Breast cancer Metastasis Response to ErbB-2-targeted therapies Transcriptional coactivator ErbB-2 signaling pathway 

Notes

Acknowledgements

We thank Mien-Chie Hung (MD Anderson Cancer Center, Houston, TX, USA) for his generous help and support during the course of our studies of ErbB-2 nuclear function. We are grateful to Valerie Paul Roux for her assistance in the preparation of the manuscript. We thank René Barón Foundation and Willliams Foundation for their institutional support.

Funding Information

This work was supported by IDB/PICT 2015–1587, IDB/PICT 2012-668, and PID 2012-066 grants from the National Agency of Scientific Promotion of Argentina (ANPCyT); by a grant from the Nelia and Amadeo Barletta Foundation from Switzerland; and by a grant from the National Institute of Cancer from Argentina, all of them awarded to PVE. RICR was awarded with an early career research grant from AJ Roemmers Foundation.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Slamon DJ, Godolphin W, Jones LA, Holt JA, Wong SG, Keith DE, Levin WJ, Stuart SG, Udove J, Ullrich A (1989) Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 244(4905):707–712CrossRefGoogle Scholar
  2. 2.
    Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, Baselga J, Norton L (2001) Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344(11):783–792.  https://doi.org/10.1056/NEJM200103153441101 CrossRefPubMedGoogle Scholar
  3. 3.
    Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE Jr, Davidson NE, Tan-Chiu E, Martino S, Paik S, Kaufman PA, Swain SM, Pisansky TM, Fehrenbacher L, Kutteh LA, Vogel VG, Visscher DW, Yothers G, Jenkins RB, Brown AM, Dakhil SR, Mamounas EP, Lingle WL, Klein PM, Ingle JN, Wolmark N (2005) Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 353(16):1673–1684.  https://doi.org/10.1056/NEJMoa052122 CrossRefGoogle Scholar
  4. 4.
    Esteva FJ, Valero V, Booser D, Guerra LT, Murray JL, Pusztai L, Cristofanilli M, Arun B, Esmaeli B, Fritsche HA, Sneige N, Smith TL, Hortobagyi GN (2002) Phase II study of weekly docetaxel and trastuzumab for patients with HER-2-overexpressing metastatic breast cancer. J Clin Oncol 20(7):1800–1808.  https://doi.org/10.1200/JCO.2002.07.058 CrossRefPubMedGoogle Scholar
  5. 5.
    Geyer CE, Forster J, Lindquist D, Chan S, Romieu CG, Pienkowski T, Jagiello-Gruszfeld A, Crown J, Chan A, Kaufman B, Skarlos D, Campone M, Davidson N, Berger M, Oliva C, Rubin SD, Stein S, Cameron D (2006) Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 355(26):2733–2743.  https://doi.org/10.1056/NEJMoa064320 CrossRefPubMedGoogle Scholar
  6. 6.
    Krop IE, Kim SB, Gonzalez-Martin A, LoRusso PM, Ferrero JM, Smitt M, Yu R, Leung AC, Wildiers H (2014) Trastuzumab emtansine versus treatment of physician's choice for pretreated HER2-positive advanced breast cancer (TH3RESA): a randomised, open-label, phase 3 trial. Lancet Oncol 15(7):689–699.  https://doi.org/10.1016/S1470-2045(14)70178-0 CrossRefPubMedGoogle Scholar
  7. 7.
    Esteva FJ, Yu D, Hung MC, Hortobagyi GN (2010) Molecular predictors of response to trastuzumab and lapatinib in breast cancer. Nat Rev Clin Oncol 7(2):98–107.  https://doi.org/10.1038/nrclinonc.2009.216 CrossRefPubMedGoogle Scholar
  8. 8.
    Singh JC, Jhaveri K, Esteva FJ (2014) HER2-positive advanced breast cancer: optimizing patient outcomes and opportunities for drug development. Br J Cancer 111(10):1888–1898 https://dx.doi.org/10.1038%2Fbjc.2014.388 CrossRefGoogle Scholar
  9. 9.
    Wang SC, Lien HC, Xia W, Chen IF, Lo HW, Wang Z, Ali-Seyed M, Lee DF, Bartholomeusz G, Ou-Yang F, Giri DK, Hung MC (2004) Binding at and transactivation of the COX-2 promoter by nuclear tyrosine kinase receptor ErbB-2. Cancer Cell 6(3):251–261.  https://doi.org/10.1016/j.ccr.2004.07.012 CrossRefPubMedGoogle Scholar
  10. 10.
    Tzahar E, Waterman H, Chen X, Levkowitz G, Karunagaran D, Lavi S, Ratzkin BJ, Yarden Y (1996) A hierarchical network of interreceptor interactions determines signal transduction by Neu differentiation factor/neuregulin and epidermal growth factor. Mol Cell Biol 16(10):5276–5287CrossRefGoogle Scholar
  11. 11.
    Graus-Porta D, Beerli RR, Daly JM, Hynes NE (1997) ErbB-2, the preferred heterodimerization partner of all ErbB receptors, is a mediator of lateral signaling. EMBO J 16(7):1647–1655.  https://doi.org/10.1093/emboj/16.7.1647 CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Tao RH, Maruyama IN (2008) All EGF(ErbB) receptors have preformed homo- and heterodimeric structures in living cells. J Cell Sci 121(Pt 19):3207–3217.  https://doi.org/10.1242/jcs.033399 CrossRefPubMedGoogle Scholar
  13. 13.
    Balana ME, Labriola L, Salatino M, Movsichoff F, Peters G, Charreau EH, Elizalde PV (2001) Activation of ErbB-2 via a hierarchical interaction between ErbB-2 and type I insulin-like growth factor receptor in mammary tumor cells. Oncogene 20(1):34–47CrossRefGoogle Scholar
  14. 14.
    Salatino M, Schillaci R, Proietti CJ, Carnevale R, Frahm I, Molinolo AA, Iribarren A, Charreau EH, Elizalde PV (2004) Inhibition of in vivo breast cancer growth by antisense oligodeoxynucleotides to type I insulin-like growth factor receptor mRNA involves inactivation of ErbBs, PI-3K/Akt and p42/p44 MAPK signaling pathways but not modulation of progesterone receptor activity. Oncogene 23(30):5161–5174.  https://doi.org/10.1038/sj.onc.1207659 CrossRefPubMedGoogle Scholar
  15. 15.
    Labriola L, Salatino M, Proietti CJ, Pecci A, Coso OA, Kornblihtt AR, Charreau EH, Elizalde PV (2003) Heregulin induces transcriptional activation of the progesterone receptor by a mechanism that requires functional ErbB-2 and mitogen-activated protein kinase activation in breast cancer cells. Mol Cell Biol 23(3):1095–1111CrossRefGoogle Scholar
  16. 16.
    Proietti CJ, Rosemblit C, Beguelin W, Rivas MA, Diaz Flaque MC, Charreau EH, Schillaci R, Elizalde PV (2009) Activation of Stat3 by heregulin/ErbB-2 through the co-option of progesterone receptor signaling drives breast cancer growth. Mol Cell Biol 29(5):1249–1265.  https://doi.org/10.1128/MCB.00853-08 CrossRefPubMedGoogle Scholar
  17. 17.
    Olayioye MA, Neve RM, Lane HA, Hynes NE (2000) The ErbB signaling network: receptor heterodimerization in development and cancer. EMBO J 19(13):3159–3167.  https://doi.org/10.1093/emboj/19.13.3159 CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Ranger JJ, Levy DE, Shahalizadeh S, Hallett M, Muller WJ (2009) Identification of a Stat3-dependent transcription regulatory network involved in metastatic progression. Cancer Res 69(17):6823–6830.  https://doi.org/10.1158/0008-5472.CAN-09-1684 CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Cordo Russo RI, Beguelin W, Diaz Flaque MC, Proietti C, Venturutti L, Galigniana NM, Tkach M, Guzman P, Roa JC, O'Brien N, Charreau EH, Schillaci R, Elizalde PV (2015) Targeting ErbB-2 nuclear localization and function inhibits breast cancer growth and overcomes trastuzumab resistance. Oncogene 34(26):3413–3428.  https://doi.org/10.1038/onc.2014.272 CrossRefPubMedGoogle Scholar
  20. 20.
    Beguelin W, Diaz Flaque MC, Proietti CJ, Cayrol F, Rivas MA, Tkach M, Rosemblit C, Tocci JM, Charreau EH, Schillaci R, Elizalde PV (2010) 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 30(23):5456–5472.  https://doi.org/10.1128/MCB.00012-10 CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Li LY, Chen H, Hsieh YH, Wang YN, Chu HJ, Chen YH, Chen HY, Chien PJ, Ma HT, Tsai HC, Lai CC, Sher YP, Lien HC, Tsai CH, Hung MC (2011) Nuclear ErbB2 enhances translation and cell growth by activating transcription of ribosomal RNA genes. Cancer Res 71(12):4269–4279.  https://doi.org/10.1158/0008-5472.CAN-10-3504 CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Li X, Kuang J, Shen Y, Majer MM, Nelson CC, Parsawar K, Heichman KA, Kuwada SK (2012) The atypical histone macroH2A1.2 interacts with HER-2 protein in cancer cells. J Biol Chem 287(27):23171–23183.  https://doi.org/10.1074/jbc.M112.379412 CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Venturutti L, Romero LV, Urtreger AJ, Chervo MF, Cordo Russo RI, Mercogliano MF, Inurrigarro G, Pereyra MG, Proietti CJ, Izzo F, Diaz Flaque MC, Sundblad V, Roa JC, Guzman P, Bal de Kier Joffe ED, Charreau EH, Schillaci R, Elizalde PV (2016) 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(17):2208–2222.  https://doi.org/10.1038/onc.2015.281 CrossRefPubMedGoogle Scholar
  24. 24.
    Tan M, Jing T, Lan KH, Neal CL, Li P, Lee S, Fang D, Nagata Y, Liu J, Arlinghaus R, Hung MC, Yu D (2002) Phosphorylation on tyrosine-15 of p34(Cdc2) by ErbB2 inhibits p34(Cdc2) activation and is involved in resistance to taxol-induced apoptosis. Mol Cell 9(5):993–1004CrossRefGoogle Scholar
  25. 25.
    Kim HP, Yoon YK, Kim JW, Han SW, Hur HS, Park J, Lee JH, Oh DY, Im SA, Bang YJ, Kim TY (2009) Lapatinib, a dual EGFR and HER2 tyrosine kinase inhibitor, downregulates thymidylate synthase by inhibiting the nuclear translocation of EGFR and HER2. PLoS One 4(6):e5933.  https://doi.org/10.1371/journal.pone.0005933 CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Diaz Flaque MC, Galigniana NM, Beguelin W, Vicario R, Proietti CJ, Russo RC, Rivas MA, Tkach M, Guzman P, Roa JC, Maronna E, Pineda V, Munoz S, Mercogliano MF, Charreau EH, Yankilevich P, Schillaci R, Elizalde PV (2013) 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 15(6):R118.  https://doi.org/10.1186/bcr3587 CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Diaz Flaque MC, Vicario R, Proietti CJ, Izzo F, Schillaci R, Elizalde PV (2013) 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 78(6):559–567.  https://doi.org/10.1016/j.steroids.2012.11.003 CrossRefPubMedGoogle Scholar
  28. 28.
    Schillaci R, Guzman P, Cayrol F, Beguelin W, Diaz Flaque MC, Proietti CJ, Pineda V, Palazzi J, Frahm I, Charreau EH, Maronna E, Roa JC, Elizalde PV (2012) Clinical relevance of ErbB-2/HER2 nuclear expression in breast cancer. BMC Cancer 12(1):74.  https://doi.org/10.1186/1471-2407-12-74 CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Wang YN, Yamaguchi H, Huo L, Du Y, Lee HJ, Lee HH, Wang H, Hsu JM, Hung MC (2010) The translocon Sec61beta localized in the inner nuclear membrane transports membrane-embedded EGF receptor to the nucleus. J Biol Chem 285(49):38720–38729.  https://doi.org/10.1074/jbc.M110.158659 CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Carpenter G, Liao HJ (2013) Receptor tyrosine kinases in the nucleus. Cold Spring Harb Perspect Biol 5(10):a008979 https://dx.doi.org/10.1101%2Fcshperspect.a008979 CrossRefGoogle Scholar
  31. 31.
    Chen MK, Hung MC (2015) Proteolytic cleavage, trafficking, and functions of nuclear receptor tyrosine kinases. FEBS J 282(19):3693–3721.  https://doi.org/10.1111/febs.13342 CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Giri DK, Ali-Seyed M, Li LY, Lee DF, Ling P, Bartholomeusz G, Wang SC, Hung MC (2005) Endosomal transport of ErbB-2: mechanism for nuclear entry of the cell surface receptor. Mol Cell Biol 25(24):11005–11018.  https://doi.org/10.1128/MCB.25.24.11005-11018.2005 CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Sheng C, Qiu J, He Z, Wang H, Wang Q, Guo Z, Zhu L, Ni Q (2018) Suppression of Kpnbeta1 expression inhibits human breast cancer cell proliferation by abrogating nuclear transport of Her2. Oncol Rep 39(2):554–564.  https://doi.org/10.3892/or.2017.6151 CrossRefPubMedGoogle Scholar
  34. 34.
    Marfori M, Mynott A, Ellis JJ, Mehdi AM, Saunders NF, Curmi PM, Forwood JK, Bodén M, Kobe B (2011) Molecular basis for specificity of nuclear import and prediction of nuclear localization. Biochim Biophys Acta 1813(9):1562–1577.  https://doi.org/10.1016/j.bbamcr.2010.10.013 CrossRefPubMedGoogle Scholar
  35. 35.
    Balana ME, Lupu R, Labriola L, Charreau EH, Elizalde PV (1999) Interactions between progestins and heregulin (HRG) signaling pathways: HRG acts as mediator of progestins proliferative effects in mouse mammary adenocarcinomas. Oncogene 18(46):6370–6379.  https://doi.org/10.1038/sj.onc.1203028 CrossRefPubMedGoogle Scholar
  36. 36.
    Proietti C, Salatino M, Rosemblit C, Carnevale R, Pecci A, Kornblihtt AR, Molinolo AA, Frahm I, Charreau EH, Schillaci R, Elizalde PV (2005) Progestins induce transcriptional activation of signal transducer and activator of transcription 3 (Stat3) via a Jak- and Src-dependent mechanism in breast cancer cells. Mol Cell Biol 25(12):4826–4840.  https://doi.org/10.1128/MCB.25.12.4826-4840.2005 CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Huang TH, Wu F, Loeb GB, Hsu R, Heidersbach A, Brincat A, Horiuchi D, Lebbink RJ, Mo YY, Goga A, McManus MT (2009) Up-regulation of miR-21 by HER2/neu signaling promotes cell invasion. J Biol Chem 284(27):18515–18524.  https://doi.org/10.1074/jbc.M109.006676 CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Wang SC, Hung MC (2009) Nuclear translocation of the epidermal growth factor receptor family membrane tyrosine kinase receptors. Clin Cancer Res 15(21):6484–6489.  https://doi.org/10.1158/1078-0432.CCR-08-2813 CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Nagata Y, Lan KH, Zhou X, Tan M, Esteva FJ, Sahin AA, Klos KS, Li P, Monia BP, Nguyen NT, Hortobagyi GN, Hung MC, Yu D (2004) PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell 6(2):117–127.  https://doi.org/10.1016/j.ccr.2004.06.022 CrossRefPubMedGoogle Scholar
  40. 40.
    Junttila TT, Akita RW, Parsons K, Fields C, Lewis Phillips GD, Friedman LS, Sampath D, Sliwkowski MX (2009) Ligand-independent HER2/HER3/PI3K complex is disrupted by trastuzumab and is effectively inhibited by the PI3K inhibitor GDC-0941. Cancer Cell 15(5):429–440.  https://doi.org/10.1016/j.ccr.2009.03.020 CrossRefPubMedGoogle Scholar
  41. 41.
    Ghosh R, Narasanna A, Wang SE, Liu S, Chakrabarty A, Balko JM, Gonzalez-Angulo AM, Mills GB, Penuel E, Winslow J, Sperinde J, Dua R, Pidaparthi S, Mukherjee A, Leitzel K, Kostler WJ, Lipton A, Bates M, Arteaga CL (2011) Trastuzumab has preferential activity against breast cancers driven by HER2 homodimers. Cancer Res 71(5):1871–1882.  https://doi.org/10.1158/0008-5472.CAN-10-1872 CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Yakes FM, Chinratanalab W, Ritter CA, King W, Seelig S, Arteaga CL (2002) Herceptin-induced inhibition of phosphatidylinositol-3 kinase and Akt is required for antibody-mediated effects on p27, cyclin D1, and antitumor action. Cancer Res 62(14):4132–4141PubMedGoogle Scholar
  43. 43.
    Anido J, Scaltriti M, Bech Serra JJ, Santiago JB, Todo FR, Baselga J, Arribas J (2006) Biosynthesis of tumorigenic HER2 C-terminal fragments by alternative initiation of translation. EMBO J 25(13):3234–3244.  https://doi.org/10.1038/sj.emboj.7601191 CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Scaltriti M, Rojo F, Ocana A, Anido J, Guzman M, Cortes J, Di Cosimo S, Matias-Guiu X, Cajal S, Arribas J, Baselga J (2007) Expression of p95HER2, a truncated form of the HER2 receptor, and response to anti-HER2 therapies in breast cancer. J Natl Cancer Inst 99(8):628–638.  https://doi.org/10.1093/jnci/djk134 CrossRefPubMedGoogle Scholar
  45. 45.
    Xia W, Liu Z, Zong R, Liu L, Zhao S, Bacus SS, Mao Y, He J, Wulfkuhle JD, Petricoin EF III, Osada T, Yang XY, Hartman ZC, Clay TM, Blackwell KL, Lyerly HK, Spector NL (2011) Truncated ErbB2 expressed in tumor cell nuclei contributes to acquired therapeutic resistance to ErbB2 kinase inhibitors. Mol Cancer Ther 10(8):1367–1374.  https://doi.org/10.1158/1535-7163.MCT-10-0991 CrossRefPubMedGoogle Scholar
  46. 46.
    Scaltriti M, Verma C, Guzman M, Jimenez J, Parra JL, Pedersen K, Smith DJ, Landolfi S, Cajal S, Arribas J, Baselga J (2009) Lapatinib, a HER2 tyrosine kinase inhibitor, induces stabilization and accumulation of HER2 and potentiates trastuzumab-dependent cell cytotoxicity. Oncogene 28(6):803–814.  https://doi.org/10.1038/onc.2008.432 CrossRefPubMedGoogle Scholar
  47. 47.
    Bose R, Kavuri SM, Searleman AC, Shen W, Shen D, Koboldt DC, Monsey J, Goel N, Aronson AB, Li S, Ma CX, Ding L, Mardis ER, Ellis MJ (2013) Activating HER2 mutations in HER2 gene amplification negative breast cancer. Cancer Discov 3(2):224–237.  https://doi.org/10.1158/2159-8290.CD-12-0349 CrossRefPubMedGoogle Scholar
  48. 48.
    Wang W-L, Nie L, Huynh K-T, Chen J-Y, Yao J-H, Hung M-C, Huang W-C (2018) Abstract #4018: mutations of HER2 at L755 residue results in HER2 nuclear accumulation and enhances breast cancer stem cell activity. Cancer Res 78:4018CrossRefGoogle Scholar

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Authors and Affiliations

  1. 1.Laboratory of Molecular Mechanisms of CarcinogenesisInstituto de Biología y Medicina Experimental (IBYME), CONICETBuenos AiresArgentina

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