Complexity of signal transduction mediated by ErbB2: Clues to the potential of receptor-targeted cancer therapy

  • Péter NagyEmail author
  • Attila Jenei
  • Sándor Damjanovich
  • Thomas M Jovin
  • János SzÖllÔsi


The erbB2 oncogene belongs to the type I transmembrane tyrosine kinase family of receptors. Its medical importance stems from its widespread overexpression in breast cancer. This review will focus on the signal transduction through this protein, and explains how the overexpression of erbB2 may result in poor prognosis of breast cancer, and finally it will summerize our current understanding about the therapeutic potential of receptor-targeted therapy in breast cancer. ErbB2 does not have any known ligand which is able to bind to it with high affinity. However the kinase activity of erbB2 can be activated without any ligand, if it is overexpressed, and by heteroassociation with other members of the erbB family (erbB1 or epidermal growth factor receptor, erbB3 and erbB4). This interaction substantially increases the efficiency and diversity of signal transduction through these receptor complexes. In addition, erbB2 forms large scale receptor clusters containing hundreds of proteins. These receptor islands may take part in recruiting cytosolic factors which relay the signal towards the nucleus or the cytoplasm. Overexpression of erbB2 was linked to higher transforming activity, increased metastatic potential, angiogenesis and drug resistence of breast tumor in laboratory experiments. As a corollary of these properties, erbB2 amplification is generally thought to be associated with a poor prognosis in breast cancer patients. These early findings lead to the development of antibodies that down-regulate erbB2. Such a therapeutic approach has already been found effective in experimental tumor models and in clinical trials as well. Further understanding of the importance of erbB2 and growth factor receptors in the transformation of normal cells to malignant ones may once give us a chance to cure erbB2 overexpressing breast cancer.


erbB proteins erbB2 homoassociation heteroassociation breast cancer Herceptin 


  1. 1.2
    Ahmad I, Longenecker M, Samuel J: Antibody-targeted delivery of doxorubicin entrapped in sterically stabilized liposomes can eradicate lung cancer in mice. Cancer Res 53:1484–1488, 1993.PubMedGoogle Scholar
  2. 2.2
    Alimandi M, Romano A, Curia MC, et al: Cooperative signaling of ErbB3 and ErbB2 in neoplastic transformation and human mammary carcinomas. Oncogene 10: 1813–1821, 1995.PubMedGoogle Scholar
  3. 3.2
    Allred DC, Clark GM, Molina R, et al: Overexpression of HER-2/neu and its relationship with other prognostic factors change during the progression of in situ to invasive breast cancer. Hum Pathol 23:974–979, 1992.PubMedCrossRefGoogle Scholar
  4. 4.2
    Allred DC, O’Connell P, Fuqua SA: Biomarkers in early breast neoplasia. J Cell Biochem Suppl 17G:125–131, 1993.PubMedCrossRefGoogle Scholar
  5. 5.2
    Andrulis IL, Bull SB, Blackstein ME, et al. neu/erbB-2 amplification identifies a poor-prognosis group of women with node-negative breast cancer. Toronto Breast Cancer Study Group. J Clin Oncol 16:1340–1349, 1998.PubMedGoogle Scholar
  6. 6.2
    Bacus SS, Gudkov AV, Zelnick CR, et al: Neu differentiation factor (heregulin) induces expression of intercellular adhesion molecule 1: implications for mammary tumors. Cancer Res 53:5251–5261, 1993.PubMedGoogle Scholar
  7. 7.2
    Bacus SS, Huberman E, Chin D, et al.: A ligand for the erbB- 2 oncogene product (gp30) induces differentiation of human breast cancer cells. Cell Growth Differ 3:401–411, 1992.PubMedGoogle Scholar
  8. 8.2
    Bacus SS, Stancovski I, Huberman E, et al: Tumor-inhibitory monoclonal antibodies to the HER-2/Neu receptor induce differentiation of human breast cancer cells. Cancer Res 52:2580–2589, 1992.PubMedGoogle Scholar
  9. 9.2
    Bacus SS, Yarden Y, Oren M, et al: Neu differentiation factor (Heregulin) activates a p53-dependent pathway in cancer cells. Oncogene 12:2535–2547, 1996.PubMedGoogle Scholar
  10. 10.2
    Bargmann CI, Weinberg RA: Increased tyrosine kinase activity associated with the protein encoded by the activated neu oncogene. Proc Natl Acad Sci USA 85:5394–5398, 1988.PubMedCrossRefGoogle Scholar
  11. 11.2
    Barnes DM: c-erbB-2 amplification in mammary carcinoma. J.Cell Biochem Suppl 17G:132–138, 1993.PubMedCrossRefGoogle Scholar
  12. 12.2
    Baselga J, Norton L, Albanell J et al: Recombinant humanized anti-HER2 antibody (Herceptin) enhances the antitumor activity of paclitaxel and doxorubicin against HER2/neu overexpressing human breast cancer xenografts. Cancer Res 58:2825–2831, 1998.PubMedGoogle Scholar
  13. 13.2
    Baselga J, Seidman AD, Rosen PP, et al: HER2 overexpression and paclitaxel sensitivity in breast cancer: therapeutic implications. Oncology Huntingt 11:43–48, 1997.PubMedGoogle Scholar
  14. 14.2
    Baselga J, Tripathy D, Mendelsohn J, et al: Phase II study of weekly intravenous recombinant humanized anti- p185HER2 monoclonal antibody in patients with HER2/neu- overexpressing metastatic breast cancer. J Clin Oncol 14:737–744, 1996.PubMedGoogle Scholar
  15. 15.2
    Baulida J, Kraus MH, Alimandi M, et al: All ErbB receptors other than the epidermal growth factor receptor are endocytosis impaired. J Biol Chem 271:5251–5257, 1996.PubMedCrossRefGoogle Scholar
  16. 16.2
    Beerli RR, Hynes NE: Epidermal growth factor-related peptides activate distinct subsets of ErbB receptors and differ in their biological activities. J Biol Chem 271: 6071–6076, 1996.PubMedCrossRefGoogle Scholar
  17. 17.2
    Benz CC, Scott GK, Sarup JC, et al: Estrogen-dependent, tamoxifen- resistant tumorigenic growth of MCF-7 cells transfected with HER2/neu. Breast Cancer Res Treat 24:85–95, 1993.CrossRefGoogle Scholar
  18. 18.2
    Berns EM, Foekens JA, van Staveren IL, et al: Oncogene amplification and prognosis in breast cancer: relationship with systemic treatment. Gene 159:11–18, 1995.PubMedCrossRefGoogle Scholar
  19. 19.2
    Bianco AR, De Laurentiis M, Carlomagno C: 20 year update of the Naples Gun trial of adjuvant breast cancer therapy: evidence of interaction between c-erb-B2 expression and tamoxifene efficacy. Proc Am Soc Clin Oncol 17:97a 1998.Google Scholar
  20. 20.2
    Bourguignon LY, Zhu H, Chu A, et al: Interaction between the adhesion receptor, CD44, and the oncogene product, p185HER2, promotes human ovarian tumor cell activation. J Biol Chem 272:27913–27918, 1997.PubMedCrossRefGoogle Scholar
  21. 21.2
    Brower ST, Ahmed S, Tartter PI, et al: Prognostic variables in invasive breast cancer: contribution of comedo versus noncomedo in situ component. Ann Surg Oncol 2:440–444, 1995.PubMedCrossRefGoogle Scholar
  22. 22.2
    Burke CL, Stern DF: Activation of Neu (ErbB-2) mediated by disulfide bond-induced dimerization reveals a receptor tyrosine kinase dimer interface. Mol Cell Biol 18:5371–5379, 1998.PubMedGoogle Scholar
  23. 23.2
    Campiglio M, Tagliabue E, Srinivas U, et al: Colocalization of the p185HER2 oncoprotein and integrin alpha 6 beta 4 in Calu- 3 lung carcinoma cells. J Cell Biochem 55:409–418, 1994.PubMedCrossRefGoogle Scholar
  24. 24.2
    Canman CE, Gilmer TM, Coutts SB, et al: Growth factor modulation of p53-mediated growth arrest versus apoptosis. Genes Dev 9:600–611, 1995.PubMedCrossRefGoogle Scholar
  25. 25.2
    Carraway KL, Sliwkowski MX, Akita R et al: The erbB3 gene product is a receptor for heregulin. J Biol Chem 269:14303–14306, 1994.PubMedGoogle Scholar
  26. 26.2
    Chakrabarti A, Matkó J, Rahman NA, et al: Self-association of class I major histocompatibility complex molecules in liposome and cell surface membranes. Biochemistry 31:7182–7189, 1992.PubMedCrossRefGoogle Scholar
  27. 27.2
    Chamberlin SG, Davies DE: A unified model of c-erbB receptor homo- and heterodimerisation. Biochim Biophys Acta 1384:223–232, 1998.PubMedGoogle Scholar
  28. 28.2
    Chen LI, Webster MK, Meyer AN, et al: Transmembrane domain sequence requirements for activation of the p185c-neu receptor tyrosine kinase. J Cell Biol 137:619–631, 1997.PubMedCrossRefGoogle Scholar
  29. 29.2
    Cohen BD, Kiener PA, Green JM, et al: The relationship between human epidermal growth-like factor receptor expression and cellular transformation in NIH3T3 cells. J Biol Chem 271:30897–30903, 1996.PubMedCrossRefGoogle Scholar
  30. 30.2
    Crovello CS, Lai C, Cantley LC, et al: Differential signaling by the epidermal growth factor-like growth factors neuregulin-1 and neuregulin-2. J Biol Chem 273:26954–26961, 1998.PubMedCrossRefGoogle Scholar
  31. 31.2
    D’Souza B, Berdichevsky F, Kyprianou N, et al: Collageninduced morphogenesis and expression of the alpha 2-integrin subunit is inhibited in c-erbB2-transfected human mammary epithelial cells. Oncogene 8:1797–1806, 1993.PubMedGoogle Scholar
  32. 32.2
    D’Souza B, Taylor Papadimitriou J: Overexpression of ERBB2 in human mammary epithelial cells signals inhibition of transcription of the E-cadherin gene. Proc Natl Acad Sci USA 91:7202–7206, 1994.PubMedCrossRefGoogle Scholar
  33. 33.2
    Dalifard I, Daver A, Goussard J, et al: p185 overexpression in 220 samples of breast cancer undergoing primary surgery: comparison with c-erbB-2 gene amplification. Int J Mol Med 1:855–861, 1998.PubMedGoogle Scholar
  34. 34.2
    Daly JM, Jannot CB, Beerli RR et al: Neu differentiation factor induces ErbB2 down-regulation and apoptosis of ErbB2-overexpressing breast tumor cells. Cancer Res 57:3804–3811, 1997.PubMedGoogle Scholar
  35. 35.2
    Damjanovich S, Vereb G, Schaper A, et al: Structural hierarchy in the clustering of HLA class I molecules in the plasma membrane of human lymphoblastoid cells. Proc Natl Acad Sci USA 92:1122–1126, 1995.PubMedCrossRefGoogle Scholar
  36. 36.2
    De Corte V, De Potter C, Vandenberghe D, et al: A 50 kDa protein present in conditioned medium of COLO-16 cells stimulates cell spreading and motility, and activates tyrosine phosphorylation of Neu/HER-2, in human SK-BR-3 mammary cancer cells. J Cell Sci 107:405–416, 1994.PubMedGoogle Scholar
  37. 37.2
    De Potter CR, Quatacker J: The p185erbB2 protein is localized on cell organelles involved in cell motility. Clin Exp Metastasis 11:453–461, 1993.PubMedCrossRefGoogle Scholar
  38. 38.2
    Di Fiore PP, Segatto O, Lonardo F, et al: The carboxy-terminal domains of erbB-2 and epidermal growth factor receptor exert different regulatory effects on intrinsic receptor tyrosine kinase function and transforming activity. Mol Cell Biol 10:2749–2756, 1990.PubMedGoogle Scholar
  39. 39.2
    Discafani CM, Carroll ML, Floyd MB, al: Irreversible inhibition of epidermal growth factor receptor tyrosine kinase with in vivo activity by N-[4-[(3-bromophenyl)amino]-6-quinazolinyl]- 2-butynamide (CL-387, 785). Biochem Pharmacol 57:917–925, 1999.PubMedCrossRefGoogle Scholar
  40. 40.2
    Disis ML, Grabstein KH, Cheaver MA: HER2/neu peptide vaccines elicit T cell immunity to the HER-2/neu protein in patients with breast and ovarian cancer. Proc Am Soc Clin Oncol 17:97a 1998.Google Scholar
  41. 41.2
    Drebin JA, Link VC, Stern DF, et al: Down-modulation of an oncogene protein product and reversion of the transformed phenotype by monoclonal antibodies. Cell 41:697–706, 1985.PubMedCrossRefGoogle Scholar
  42. 42.2
    Dykins R, Corbett IP, Henry JA et al: Long-term survival in breast cancer related to overexpression of the c-erbB-2 onco- protein: an immunohistochemical study using monoclonal antibody NCL-CB11. J Pathol 163:105–110, 1991.PubMedCrossRefGoogle Scholar
  43. 43.2
    Edidin M: Lipid microdomains in cell surface membranes. Curr Opin Struct Biol 7:528–532, 1997.PubMedCrossRefGoogle Scholar
  44. 44.2
    Engelman JA, Lee RJ, Karnezis A, et al: Reciprocal regulation of neu tyrosine kinase activity and caveolin-1 protein expression in vitro and in vivo. Implications for human breast cancer. J Biol Chem 273: 20448–20455, 1998.PubMedCrossRefGoogle Scholar
  45. 45.2
    Ethier SP, Langton BC, Dilts CA: Growth factor-independent proliferation of rat mammary carcinoma cells by autocrine secretion of neu-differentiation factor/heregulin and transforming growth factor-alpha. Mol Carcinog 15:134–143, 1996.PubMedCrossRefGoogle Scholar
  46. 46.2
    Falcioni R, Antonini A, Nistico P, et al: Alpha 6 beta 4 and alpha 6 beta 1 integrins associate with ErbB-2 in human carcinoma cell lines. Exp Cell Res 236:76–85, 1997.PubMedCrossRefGoogle Scholar
  47. 47.
    Fan Z, Baselga J, Masui H, et al: Antitumor effect of anti-epidermal growth factor receptor monoclonal antibodies plus cisdiamminedichloroplatinum on well established A431 cell xenografts. Cancer Res 53:4637–4642, 1993.PubMedGoogle Scholar
  48. 48.2
    Fendly BM, Winget M, Hudziak RM, et al: Characterization of murine monoclonal antibodies reactive to either the human epidermal growth factor receptor or HER2/neu gene product. Cancer Res 50: 1550–1558, 1990.PubMedGoogle Scholar
  49. 49.2
    French AR, Tadaki DK, Niyogi SK, et al: Intracellular trafficking of epidermal growth factor family ligands is directly influenced by the pH sensitivity of the receptor/ligand interaction. J Biol Chem 270:4334–4340, 1995.PubMedCrossRefGoogle Scholar
  50. 50.2
    Gadella TW, Jr.,Jovin TM: Oligomerization of epidermal growth factor receptors on A431 cells studied by time-resolved fluorescence imaging microscopy. A stereochemical model for tyrosine kinase receptor activation. J Cell Biol 129:1543–1558, 1995.PubMedCrossRefGoogle Scholar
  51. 51.2
    Gamett DC, Pearson G, Cerione RA, et al: Secondary dimerization between members of the epidermal growth factor receptor family. J Biol Chem 272:12052–12056, 1997.PubMedCrossRefGoogle Scholar
  52. 52.2
    Gassmann M, Casagranda F, Orioli D, et al: Aberrant neural and cardiac development in mice lacking the ErbB4 neuregulin receptor. Nature 378:390–394, 1995.PubMedCrossRefGoogle Scholar
  53. 53.2
    Giani C, Casalini P, Pupa SM, et al: Increased expression of c- erbB-2 in hormone-dependent breast cancer cells inhibits cell growth and induces differentiation. Oncogene 17:425–432, 1998.PubMedCrossRefGoogle Scholar
  54. 54.2
    Graus Porta D, Beerli RR, Daly JM, et al: ErbB-2, the preferred heterodimerization partner of all ErbB receptors, is a mediator of lateral signaling. EMBO J 16:1647–1655, 1997.PubMedCrossRefGoogle Scholar
  55. 55.2
    Graus Porta D, Beerli RR, Hynes NE: Single-chain antibody- mediated intracellular retention of ErbB-2 impairs Neu differentiation factor and epidermal growth factor signaling. Mol Cell Biol 15:1182–1191, 1995.PubMedGoogle Scholar
  56. 56.2
    Gronowski AM, Bertics PJ: Modulation of epidermal growth factor receptor interaction with the detergent-insoluble cytoskeleton and its effects on receptor tyrosine kinase activity. Endocrinology 136: 2198–2205, 1995.PubMedCrossRefGoogle Scholar
  57. 57.2
    Grunt TW, Saceda M, Martin MB, et al: Bidirectional interactions between the estrogen receptor and the cerbB-2 signaling pathways: heregulin inhibits estrogenic effects in breast cancer cells. Int J Cancer 63:560–567, 1995.PubMedCrossRefGoogle Scholar
  58. 58.2
    Gullick WJ: Prevalence of aberrant expression of the epidermal growth factor receptor in human cancers. Br Med Bull 47:87–98, 1991.PubMedGoogle Scholar
  59. 59.2
    Gusterson BA, Gelber RD, Goldhirsch A, et al: Prognostic importance of c-erbB-2 expression in breast cancer. International (Ludwig) Breast Cancer Study Group. J Clin Oncol 10:1049–1056, 1992.PubMedGoogle Scholar
  60. 60.2
    Haerslev T, Jacobsen GK: c-erbB-2 oncoprotein is not an independent prognostic parameter in primary breast carcinoma. An immunohistochemical study. APMIS 102:612–622, 1994.PubMedCrossRefGoogle Scholar
  61. 61.2
    Harbeck N, Dettmar P, Thomssen C, et al: Prognostic impact of tumor biological factors on survival in node-negative breast cancer. Anticancer Res 18:2187–2197, 1998.PubMedGoogle Scholar
  62. 62.2
    Harder T, Simons K: Caveolae, DIGs, and the dynamics of sphingolipid-cholesterol microdomains. Curr Opin Cell Biol 9:534–542, 1997.PubMedCrossRefGoogle Scholar
  63. 63.2
    Hartmann F, Horak EM, Cho C, et al: Effects of the tyrosinekinase inhibitor geldanamycin on ligand-induced Her-2/neu activation, receptor expression and proliferation of Her-2-positive malignant cell lines. Int J Cancer 70:221–229, 1997.PubMedCrossRefGoogle Scholar
  64. 64.2
    Heldin CH: Dimerization of cell surface receptors in signal transduction. Cell 80:213–223, 1995.PubMedCrossRefGoogle Scholar
  65. 65.2
    Hellyer NJ, Cheng K, Koland JG: ErbB3 (HER3) interaction with the p85 regulatory subunit of phosphoinositide 3-kinase. Biochem J 333:757–763, 1998.PubMedGoogle Scholar
  66. 66.2
    Houston SJ, Plunkett TA, Barnes DM, et al: Overexpression of c- erbB2 is an independent marker of resistance to endocrine therapy in advanced breast cancer. Br J Cancer 79:1220–1226, 1999.PubMedCrossRefGoogle Scholar
  67. 67.2
    Hudziak RM, Lewis GD, Winget M, et al: p185HER2 monoclonal antibody has antiproliferative effects in vitro and sensitizes human breast tumor cells to tumor necrosis factor. Mol Cell Biol 9:1165–1172, 1989.PubMedGoogle Scholar
  68. 68.2
    Hwang J, Gheber LA, Margolis L, et al: Domains in cell plasma membranes investigated by near-field scanning optical microscopy. Biophys J 74:2184–2190, 1998.PubMedCrossRefGoogle Scholar
  69. 69.2
    Hynes NE, Stern DF: The biology of erbB-2/neu/HER-2 and its role in cancer. Biochim Biophys Acta 1198:165–184, 1994.PubMedGoogle Scholar
  70. 70.2
    Kallioniemi OP, Holli K, Visakorpi T, et al: Association of c- erbB-2 protein over-expression with high rate of cell proliferation, increased risk of visceral metastasis and poor long-term survival in breast cancer. Int J Cancer 49:650–655, 1991.PubMedCrossRefGoogle Scholar
  71. 71.2
    Kameda T, Yasui W, Yoshida K, et al: Expression of ERBB2 in human gastric carcinomas: relationship between p185ERBB2 expression and the gene amplification. Cancer Res 50:8002–8009, 1990.PubMedGoogle Scholar
  72. 72.2
    Karunagaran D, Tzahar E, Beerli RR, et al: ErbB-2 is a common auxiliary subunit of NDF and EGF receptors: implications for breast cancer. EMBO J 15:254–264, 1996.PubMedGoogle Scholar
  73. 73.2
    Kenworthy AK, Edidin M: Distribution of a glycosylphos- phatidylinositol-anchored protein at the apical surface of MDCK cells examined at a resolution of <100 A using imaging fluorescence resonance energy tranfer. J Cell Biol 142:69–84, 1998.PubMedCrossRefGoogle Scholar
  74. 74.2
    Kim HH, Vijapurkar U, Hellyer NJ, et al: Signal transduction by epidermal growth factor and heregulin via the kinase-deficient ErbB3 protein. Biochem J 334:189–195, 1998.PubMedGoogle Scholar
  75. 75.2
    Kirpotin D, Park JW, Hong K, et al: Sterically stabilized anti- HER2 immunoliposomes: design and targeting to human breast cancer cells in vitro. Biochemistry 36:66–75, 1997.PubMedCrossRefGoogle Scholar
  76. 76.2
    Klapper LN, Vaisman N, Hurwitz E, et al: A subclass of tumorinhibitory monoclonal antibodies to ErbB-2/HER2 blocks crosstalk with growth factor receptors. Oncogene 14:2099–2109, 1997.PubMedCrossRefGoogle Scholar
  77. 77.2
    Knowlden JM, Gee JM, Seery L, et al: c-erbB3 and c-erbB4 expression is a feature of the endocrine responsive phenotype in clinical breast cancer. Oncogene 17:1949–1957, 1998.PubMedCrossRefGoogle Scholar
  78. 78.2
    Kraus MH, Issing W, Miki T, et al: Isolation and characterization of ERBB3, a third member of the ERBB/epidermal growth factor receptor family: evidence for overexpression in a subset of human mammary tumors. Proc Natl Acad Sci USA 86:9193–9197, 1989.PubMedCrossRefGoogle Scholar
  79. 79.2
    Kuan CT, Pastan I: Recombinant immunotoxin containing a disulfide-stabilized Fv directed at erbB2 that does not require proteolytic activation. Biochemistry 35:2872–2877, 1996.PubMedCrossRefGoogle Scholar
  80. 80.2
    Lee KF, Simon H, Chen H, et al: Requirement for neuregulin receptor erbB2 in neural and cardiac development. Nature 378:394–398, 1995.PubMedCrossRefGoogle Scholar
  81. 81.2
    Lemmon MA, Bu Z, Ladbury JE, et al: Two EGF molecules contribute additively to stabilization of the EGFR dimer. EMBO J 16:281–294, 1997.PubMedCrossRefGoogle Scholar
  82. 82.2
    Lemmon MA, Schlessinger J: Regulation of signal transduction and signal diversity by receptor oligomerization. Trends Biochem Sci 19:459–463, 1994.PubMedCrossRefGoogle Scholar
  83. 83.2
    Levkowitz G, Klapper LN, Tzahar E, et al: Coupling of the c- Cbl protooncogene product to ErbB-1/EGF-receptor but not to other ErbB proteins. Oncogene 12:1117–1125, 1996.PubMedGoogle Scholar
  84. 84.2
    Lewis GD, Figari I, Fendly B, et al: Differential responses of human tumor cell lines to anti-p185HER2 monoclonal antibodies. Cancer Immunol Immunother 37:255–263, 1993.PubMedCrossRefGoogle Scholar
  85. 85.2
    Li W, Park JW, Nuijens A, et al: Heregulin is rapidly translocated to the nucleus and its transport is correlated with c-myc induction in breast cancer cells. Oncogene 12:2473–2477, 1996.PubMedGoogle Scholar
  86. 86.2
    Lipponen HJ, Aaltomaa S, Syrjanen S, et al: c-erbB-2 oncogene related to p53 expression, cell proliferation and prognosis in breast cancer. Anticancer Res 13:1147–1152, 1993.PubMedGoogle Scholar
  87. 87.2
    Liu X, Pogo BG: Inhibition of erbB-2-positive breast cancer cell growth by erbB-2 antisense oligonucleotides. Antisense Nucleic Acid Drug Dev 6:9–16, 1996.PubMedGoogle Scholar
  88. 88.2
    Liu Y, Martindale JL, Gorospe M, et al: Regulation of p21WAF1/CIP1 expression through mitogen-activated protein kinase signaling pathway. Cancer Res 56:31–35, 1996.PubMedGoogle Scholar
  89. 89.2
    Lofts FJ, Hurst HC, Sternberg MJ, et al: Specific short transmembrane sequences can inhibit transformation by the mutant neu growth factor receptor in vitro and in vivo. Oncogene 8:2813–2820, 1993.PubMedGoogle Scholar
  90. 90.2
    Lupu R, Colomer R, Kannan B, et al: Characterization of a growth factor that binds exclusively to the erbB-2 receptor and induces cellular responses. Proc Natl Acad Sci USA 89:2287–2291, 1992.PubMedCrossRefGoogle Scholar
  91. 91.2
    Marte BM, Jeschke M, Graus Porta D, et al: Neu differentiation factor/heregulin modulates growth and differentiation of HC11 mammary epithelial cells. Mol Endocrinol 9:14–23, 1995.PubMedCrossRefGoogle Scholar
  92. 92.2
    McNeil C: Herceptin raises its sights beyond advanced breast cancer. J Natl Cancer Inst 90:882–883, 1998.PubMedCrossRefGoogle Scholar
  93. 93.2
    Meyer D, Birchmeier C: Multiple essential functions of neuregulin in development. Nature 378:386–390, 1995.PubMedCrossRefGoogle Scholar
  94. 94.2
    Murali R, Brennan PJ, Kieber Emmons T, et al: Structural analysis of p185c-neu and epidermal growth factor receptor tyrosine kinases: oligomerization of kinase domains. Proc Natl Acad Sci USA 93:6252–6257, 1996.PubMedCrossRefGoogle Scholar
  95. 95.2
    Nagy P, Bene L, Balázs M, et al: EGF-induced redistribution of erbB2 on breast tumor cells: Flow and image cytometric energy transfer measurements. Cytometry 32:120–131, 1998.PubMedCrossRefGoogle Scholar
  96. 96.2
    Nagy P, Jenei A, Kirsch AK, et al: Activation-dependent clustering of the erbB2 receptor tyrosine kinase detected by scanning near-field optical microscopy. J Cell Sci 112:1733–1741, 1999.PubMedGoogle Scholar
  97. 97.2
    Niemann C, Brinkmann V, Spitzer E, et al: Reconstitution of mammary gland development in vitro: requirement of c-met and c-erbB2 signaling for branching and alveolar morphogenesis. J Cell Biol 143:533–545, 1998.PubMedCrossRefGoogle Scholar
  98. 98.2
    Norton L: Kinetic concepts in the systemic drug therapy of breast cancer. Semin Oncol 26:11–20, 1999.PubMedGoogle Scholar
  99. 99.2
    Nowak F, Jacquemin Sablon A, Pierre J: Expression of the activated p185erbB2 tyrosine kinase in human epithelial cells leads to MAP kinase activation but does not confer oncogenicity. Exp Cell Res 231:251–259, 1997.PubMedCrossRefGoogle Scholar
  100. 100.2
    Olayioye MA, Graus Porta D, Beerli RR, et al: ErbB-1 and ErbB-2 acquire distinct signaling properties dependent upon their dimerization partner. Mol Cell Biol 18:5042–5051, 1998.PubMedGoogle Scholar
  101. 101.2
    Ouyang X, Gulliford T, Huang G, et al: Transforming growth factor-alpha short-circuits downregulation of the epidermal growth factor receptor. J Cell Physiol 179:52–57, 1999.PubMedCrossRefGoogle Scholar
  102. 102.2
    Papahadjopoulos D, Allen TM, Gabizon A, et al: Sterically stabilized liposomes: improvements in pharmacokinetics and antitumor therapeutic efficacy. Proc Natl Acad Sci USA 88:11460–11464, 1991.PubMedCrossRefGoogle Scholar
  103. 103.2
    Park JW, Hong K, Carter P: Development of anti-p185HER2 immunoliposomes for cancer therapy. Proc Natl Acad Sci USA 92:1327–1331, 1995.PubMedCrossRefGoogle Scholar
  104. 104.2
    Pegram MD, Finn RS, Arzoo K, et al: The effect of HER-2/neu overexpression on chemotherapeutic drug sensitivity in human breast and ovarian cancer cells. Oncogene 15:537–547, 1997.PubMedCrossRefGoogle Scholar
  105. 105.2
    Pegram MD, Lipton A, Hayes DF, et al: Phase II study of receptor-enhanced chemosensitivity using recombinant humanized anti-p185HER2/neu monoclonal antibody plus cisplatin in patients with HER2/neu-overexpressing metastatic breast cancer refractory to chemotherapy treatment. J Clin Oncol 16:2659–2671, 1998.PubMedGoogle Scholar
  106. 106.2
    Peiper M, Goedegebuure PS, Linehan DC, et al: The HER2/neuderived peptide p654-662 is a tumor-associated antigen in human pancreatic cancer recognized by cytotoxic T lymphocytes. Eur J Immunol 27:1115–1123, 1997.PubMedCrossRefGoogle Scholar
  107. 107.2
    Petit AM, Rak J, Hung MC, et al: Neutralizing antibodies against epidermal growth factor and ErbB-2/neu receptor tyrosine kinases down-regulate vascular endothelial growth factor production by tumor cells in vitro and in vivo: angiogenic implications for signal transduction therapy of solid tumors. Am J Pathol 151:1523–1530, 1997.PubMedGoogle Scholar
  108. 108.2
    Pietras RJ, Arboleda J, Reese DM, et al: HER-2 tyrosine kinase pathway targets estrogen receptor and promotes hormone- independent growth in human breast cancer cells. Oncogene 10:2435–2446, 1995.PubMedGoogle Scholar
  109. 109.2
    Pietras RJ, Fendly BM, Chazin VR, et al: Antibody to HER- 2/neu receptor blocks DNA repair after cisplatin in human breast and ovarian cancer cells. Oncogene 9:1829–1838, 1994.PubMedGoogle Scholar
  110. 110.2
    Pietras RJ, Pegram MD, Finn RS, et al: Remission of human breast cancer xenografts on therapy with humanized monoclonal antibody to HER-2 receptor and DNA-reactive drugs. Oncogene 17:2235–2249, 1998.PubMedCrossRefGoogle Scholar
  111. 111.2
    Pinkas Kramarski R, Shelly M, Glathe S, et al: Neu differentiation factor/neuregulin isoforms activate distinct receptor combinations. J Biol Chem 271:19029–19032, 1996.PubMedCrossRefGoogle Scholar
  112. 112.2
    Plowman GD, Culouscou JM, Whitney GS, et al: Ligand-specific activation of HER4/p180erbB4, a fourth member of the epidermal growth factor receptor family. Proc Natl Acad Sci USA 90:1746–1750, 1993.PubMedCrossRefGoogle Scholar
  113. 113.2
    Press MF, Hung G, Godolphin W, et al: Sensitivity of HER- 2/neu antibodies in archival tissue samples: potential source of error in immunohistochemical studies of oncogene expression. Cancer Res 54:2771–2777, 1994.PubMedGoogle Scholar
  114. 114.2
    Press MF, Pike MC, Chazin VR, et al: Her-2/neu expression in node-negative breast cancer: direct tissue quantitation by computerized image analysis and association of overexpression with increased risk of recurrent disease. Cancer Res 53:4960–4970, 1993.PubMedGoogle Scholar
  115. 115.2
    Qian X, Dougall WC, Hellman ME, et al: Kinase-deficient neu proteins suppress epidermal growth factor receptor function and abolish cell transformation. Oncogene 9:1507–1514, 1994.PubMedGoogle Scholar
  116. 116.2
    Qian X, O’Rourke DM, Fei Z, et al: Domain-specific interactions between the p185(neu) and epidermal growth factor receptor kinases determine differential signaling outcomes. J Biol Chem 274: 574–583, 1999.PubMedCrossRefGoogle Scholar
  117. 117.2
    Quenel N, Wafflart J, Bonichon F, et al: The prognostic value of c-erbB2 in primary breast carcinomas: a study on 942 cases. Breast Cancer Res Treat 35:283–291, 1995.PubMedCrossRefGoogle Scholar
  118. 118.2
    Revillion F, Bonneterre J, Peyrat JP: ERBB2 oncogene in human breast cancer and its clinical significance. Eur J Cancer 34:791–808, 1998.PubMedCrossRefGoogle Scholar
  119. 119.2
    Riethmacher D, Sonnenberg Riethmacher E, et al: Severe neuropathies in mice with targeted mutations in the ErbB3 receptor. Nature 389:725–730, 1997.PubMedCrossRefGoogle Scholar
  120. 120.2
    Ross JS, Fletcher JA: The HER-2/neu oncogene in breast cancer: prognostic factor, predictive factor, and target for therapy. Stem Cells 16:413–428, 1998.PubMedCrossRefGoogle Scholar
  121. 121.2
    Sarup JC, Johnson RM, King K, et al: Characterization of an anti-p185HER2 monoclonal antibody that stimulates receptor function and inhibits tumor cell growth. Growth Regul 1:72–82, 1991.PubMedGoogle Scholar
  122. 122.2
    Schechter AL, Hung MC, Vaidyanathan L, et al: The neu gene: an erbB-homologous gene distinct from and unlinked to the gene encoding the EGF receptor. Science 229:976–978, 1985.PubMedCrossRefGoogle Scholar
  123. 123.2
    Schroeder JA, Lee DC: Dynamic expression and activation of ERBB receptors in the developing mouse mammary gland. Cell Growth Differ 9:451–464, 1998.PubMedGoogle Scholar
  124. 124.
    Shackney SE, A, Smith CA, et al: Intracellular coexpression of epidermal growth factor receptor, Her-2/neu, and p21ras in human breast cancers: evidence for the existence of distinctive patterns of genetic evolution that are common to tumors from different patients. Clin Cancer Res 4:913–928, 1998.PubMedGoogle Scholar
  125. 125.2
    Shelly M, Pinkas Kramarski R, Guarino BC, et al: Epiregulin is a potent pan-ErbB ligand that preferentially activates heterodimeric receptor complexes. J Biol Chem 273:10496–10505, 1998.PubMedCrossRefGoogle Scholar
  126. 126.2
    Silletti S, Paku S, Raz A: Tumor cell motility and metastasis. Autocrine motility factor as an example of ecto/exoenzyme cytokines. Pathol Oncol Res 3:230–254, 1997.PubMedCrossRefGoogle Scholar
  127. 127.2
    Simons K, Ikonen E: Functional rafts in cell membranes. Nature 387:569–572, 1997.PubMedCrossRefGoogle Scholar
  128. 128.2
    Sjogren S, Inganas M, Lindgren A, et al: Prognostic and predictive value of c-erbB-2 overexpression in primary breast cancer, alone and in combination with other prognostic markers. J Clin Oncol 16:462–469, 1998.PubMedGoogle Scholar
  129. 129.2
    Skarpen E, Johannessen LE, Bjerk K, et al: Endocytosed epidermal growth factor (EGF) receptors contribute to the EGF- mediated growth arrest in A431 cells by inducing a sustained increase in p21/CIP1. Exp Cell Res 243:161–172, 1998.PubMedCrossRefGoogle Scholar
  130. 130.2
    Slamon DJ, Clark GM, Wong SG, et al: Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235: 177–182, 1987.PubMedCrossRefGoogle Scholar
  131. 131.2
    Sliwkowski MX, Schaefer G, Akita RW, et al: Coexpression of erbB2 and erbB3 proteins reconstitutes a high affinity receptor for heregulin. J Biol Chem 269:14661–14665, 1994.PubMedGoogle Scholar
  132. 132.2
    Soltoff SP, Carraway KL, Prigent SA, et al: ErbB3 is involved in activation of phosphatidylinositol 3-kinase by epidermal growth factor. Mol Cell Biol 14:3550–3558, 1994.PubMedGoogle Scholar
  133. 133.2
    Srinivasan R, Poulsom R, Hurst HC, et al: Expression of the c-erbB-4/HER4 protein and mRNA in normal human fetal and adult tissues and in a survey of nine solid tumour types. J Pathol 185:236–245, 1998.PubMedCrossRefGoogle Scholar
  134. 134.2
    Stancovski I, Hurwitz E, Leitner O, et al: Mechanistic aspects of the opposing effects of monoclonal antibodies to the ERBB2 receptor on tumor growth. Proc Natl Acad Sci USA 88:8691–8695, 1991.PubMedCrossRefGoogle Scholar
  135. 135.2
    Szöllôsi J, Balázs M, Feuerstein BG, et al: ERBB-2 (HER2/neu) gene copy number, p185HER-2 overexpression, and intratumor heterogeneity in human breast cancer. Cancer Res 55:5400–5407, 1995.PubMedGoogle Scholar
  136. 136.2
    Szöllôsi J, Horejsi V, Bene L, et al: Supramolecular complexes of MHC class I, MHC class II, CD20, and tetraspan molecules (CD53, CD81, and CD82) at the surface of a B cell line JY. J Immunol 157:2939–2946, 1996.PubMedGoogle Scholar
  137. 137.2
    Tagliabue E, Centis F, Campiglio M, et al: Selection of monoclonal antibodies which induce internalization and phosphorylation of p185HER2 and growth inhibition of cells with HER2/NEU gene amplification. Int J Cancer 47:933–937, 1991.PubMedCrossRefGoogle Scholar
  138. 138.2
    Tan M, Grijalva R, Yu D: Heregulin beta1-activated phosphatidylinositol 3-kinase enhances aggregation of MCF-7 breast cancer cells independent of extracellular signal-regulated kinase. Cancer Res 59:1620–1625, 1999.PubMedGoogle Scholar
  139. 139.2
    Tan M, Yao J, Yu D: Overexpression of the c-erbB-2 gene enhanced intrinsic metastasis potential in human breast cancer cells without increasing their transformation abilities. Cancer Res 57:1199–1205, 1997.PubMedGoogle Scholar
  140. 140.2
    Taylor SL, Platt Higgins A, Rudland PS, et al: Cytoplasmic staining of c-erbB-2 is not associated with the presence of detectable c-erbB-2 mRNA in breast cancer specimens. Int J Cancer 76:459–463, 1998.PubMedCrossRefGoogle Scholar
  141. 141.2
    Tetu B, Brisson J: Prognostic significance of HER-2/neu oncoprotein expression in node-positive breast cancer. The influence of the pattern of immunostaining and adjuvant therapy. Cancer 73:2359–2365, 1994.PubMedCrossRefGoogle Scholar
  142. 142.2
    Timar J, Trikha M, Szekeres K, et al: Expression and function of the high affinity alphaIIbbeta3 integrin in murine melanoma cells. Clin Exp Metastasis 16:437–445, 1998.PubMedCrossRefGoogle Scholar
  143. 143.2
    Tiwari RK, Borgen PI, Wong GY, et al: HER-2/neu amplification and overexpression in primary human breast cancer is associated with early metastasis. Anticancer Res 12:419–425, 1992.PubMedGoogle Scholar
  144. 144.2
    Tzahar E, Pinkas Kramarski R, et al: Bivalence of EGF-like ligands drives the ErbB signaling network. EMBO J 16:4938–4950, 1997.PubMedCrossRefGoogle Scholar
  145. 145.2
    Tzahar E, Waterman H, Chen X, et al: A hierarchical network of interreceptor interactions determines signal transduction by Neu differentiation factor/neuregulin and epidermal growth factor. Mol Cell Biol 16:5276–5287, 1996.PubMedGoogle Scholar
  146. 146.2
    Vaughn JP, Iglehart JD, Demirdji S et al: Antisense DNA downregulation of the ERBB2 oncogene measured by a flow cytometric assay. Proc Natl Acad Sci USA 92:8338–8342, 1995.PubMedCrossRefGoogle Scholar
  147. 147.2
    Verbeek BS, Adriaansen Slot SS, Vroom TM, et al: Overexpression of EGFR and c-erbB2 causes enhanced cell migration in human breast cancer cells and NIH3T3 fibroblasts. FEBS Lett 425:145–150, 1998.PubMedCrossRefGoogle Scholar
  148. 148.2
    Warri AM, Laine AM, Majasuo KE, et al: Estrogen suppression of erbB2 expression is associated with increased growth rate of ZR-75-1 human breast cancer cells in vitro and in nude mice. Int J Cancer 49:616–623, 1991.PubMedCrossRefGoogle Scholar
  149. 149.2
    Waterman H, Sabanai I, Geiger B, et al: Alternative intracellular routing of ErbB receptors may determine signaling potency. J Biol Chem 273:13819–13827, 1998.PubMedCrossRefGoogle Scholar
  150. 150.2
    Wiechen K, Zimmer C, Dietel M: Selection of a high activity c-erbB-2 ribozyme using a fusion gene of c-erbB-2 and the enhanced green fluorescent protein. Cancer Gene Ther 5:45–51, 1998.PubMedGoogle Scholar
  151. 151.2
    Willsher PC, Pinder SE, Gee JM, et al: C-erbB2 expression predicts response to preoperative chemotherapy for locally advanced breast cancer. Anticancer Res 18:3695–3698, 1998.PubMedGoogle Scholar
  152. 152.2
    Witters LM, Kumar R, Chinchilli VM, et al: Enhanced antiproliferative activity of the combination of tamoxifen plus HER-2-neu antibody. Breast Cancer Res Treat 42:1–5, 1997.PubMedCrossRefGoogle Scholar
  153. 153.2
    Worthylake R, Opresko LK, Wiley HS: ErbB-2 amplification inhibits down-regulation and induces constitutive activation of both erbB-2 and epidermal growth factor receptors. J Biol Chem 274:8865–8874, 1999.PubMedCrossRefGoogle Scholar
  154. 154.2
    Wright C, Cairns J, Cantwell BJ, et al: Response to mitoxantrone in advanced breast cancer: correlation with expression of c-erbB-2 protein and glutathione S-transferases. Br J Cancer 65:271–274, 1992.PubMedGoogle Scholar
  155. 155.2
    Ye D, Mendelsohn J, Fan Z: Augmentation of a humanized anti-HER2 mAb 4D5 induced growth inhibition by a humanmouse chimeric anti-EGF receptor mAb C225. Oncogene 18:731–738, 1999.PubMedCrossRefGoogle Scholar
  156. 156.2
    Yen L, Nie ZR, You XL, et al: Regulation of cellular response to cisplatin-induced DNA damage and DNA repair in cells overexpressing p185(erbB-2) is dependent on the ras signaling pathway. Oncogene 14:1827–1835, 1997.PubMedCrossRefGoogle Scholar
  157. 157.2
    Yu D, Liu B, Tan M, et al: Overexpression of c-erbB-2/neu in breast cancer cells confers increased resistance to Taxol via mdr1- independent mechanisms. Oncogene 13:1359–1365, 1996.PubMedGoogle Scholar
  158. 158.2
    Zafrani B, Leroyer A, Fourquet A, et al: Mammographically- detected ductal in situ carcinoma of the breast analyzed with a new classification. A study of 127 cases: correlation with estrogen and progesterone receptors, p53 and c-erbB-2 proteins, and proliferative activity. Semin Diagn Pathol 11:208–214, 1994.PubMedGoogle Scholar
  159. 159.2
    Zidovetzki R, Johnson DA, Arndt Jovin DJ, et al: Rotational mobility of high-affinity epidermal growth factor receptors on the surface of living A431 cells. Biochemistry 30:6162–6166, 1991.PubMedCrossRefGoogle Scholar
  160. 160.2
    Zidovetzki R, Yarden Y, Schlessinger J, et al: Microaggregation of hormone-occupied epidermal growth factor receptors on plasma membrane preparations. EMBO J 5:247–250, 1986.PubMedGoogle Scholar

Copyright information

© W. B. Saunders & Company Ltd 1999

Authors and Affiliations

  • Péter Nagy
    • 1
    • 2
    • 3
    Email author
  • Attila Jenei
    • 1
    • 3
  • Sándor Damjanovich
    • 1
  • Thomas M Jovin
    • 3
  • János SzÖllÔsi
    • 1
  1. 1.Department of Biophysics and Cell BiologyUniversity Medical School of DebrecenDebrecenHungary
  2. 2.Biophysical WorkgroupHungarian Academy of SciencesHungary
  3. 3.Department of Molecular BiologyMax Planck Institute for Biophysical ChemistryGöttingenGermany

Personalised recommendations