Human epidermal growth factor receptor-2 (HER2/erbB-2) belongs to a family of four transmembrane receptors involved in signal transduction pathways that regulate cell growth and differentiation. Overexpression/amplification of HER2 is associated with malignancy and a poor prognosis in breast cancer. HER2 acts as a networking receptor that mediates signaling to cancer cells, causing them to proliferate. HER receptors exist as monomers but dimerize on ligand binding. HER ligands are bivalent growth factor molecules whose low-affinity site binds to HER2. No HER2-specific ligand has been identified but HER2 is the preferred heterodimerization partner for other HER receptors. HER2-containing heterodimers are relatively long-lived and potent. HER3 has no inherent activity and is the major and most potent dimerization partner of HER2. HER2 overexpression biases the formation of HER2-containing heterodimers, leading to enhanced responsiveness to stromal growth factors and oncogenic transformation. Removal of HER2 from the cell surface or inhibition of its intrinsic enzymatic activity may reduce oncogenicity. Our research suggests that the antitumor efficacy of HER2-specific antibodies such as Herceptin® relates to their ability to direct HER2 to a Cbl- dependent endocytosis and degradation pathway. The reported clinical therapeutic efficacy of anti-HER2 monoclonal antibodies in breast cancer highlights the importance of understanding the biology of HER2.

Keywords:
HER2 (erbB-2, neu), Receptor, Tumor growth, Breast cancer, Monoclonal antibody, Herceptin®, Trastuzumab, Network, Signaling
1.
Akiyama T, Saito T, Ogawara H, Toyoshima K, Yamamoto T: Tumor promoter and epidermal growth factor stimulate phosphorylation of the c-erbB-2 gene product in MKN-7 human adenocarcinoma cells. Mol Cell Biol 1988;8:1019–1026.
2.
Akiyama T, Sudo C, Ogawara H, Toyoshima K, Yamamoto T: The product of the human c-erbB-2 gene: A 185-kilodalton glycoprotein with tyrosine kinase activity. Science 1986;232:1644–1646.
3.
Alimandi M, Romano A, Curia MC, Muraro R, Fedi P, Aaronson SA, Di Fiore PP, Kraus MH: Cooperative signaling of erbB3 and erbB2 in neoplastic transformation and human mammary carcinomas. Oncogene 1985;10:1813–1821.
4.
Allred DC, Clarke GM, Molina R, Tandon AK, Schnitt SJ, Gilchrist KW, Osborne CK, Tormey DC, McGuire WL: 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 1992;23:974–979.
5.
Alroy I, Yarden Y: The ErbB signaling network in embryogenesis and oncogenesis: signal diversification through combinatorial ligand-receptor interactions. FEBS Lett 1997;410:83–86.
6.
American Society of Clinical Oncology (ASCO): 1997 update of recommendations for the use of tumour markers in breast and colorectal cancer. J Clin Oncol 1998;16:793–795.
7.
Baly DL, Wirth CM, Allison DA et al: Development and characterization of a rhuMAb HER2 antibody assay for clinical evaluation of cytotoxic potency. Proc Am Assoc Cancer Res 1997;38:181A.
8.
Bargmann CI, Hung MC, Weinberg RA: The neu oncogene encodes an epidermal growth factor receptor-related protein. Nature 1986;319:226–230.
9.
Baselga J: Herceptin® alone or in combination with chemotherapy in the treatment of HER2-positive metastatic breast cancer: pivotal trials. Oncology 2001;61(suppl 2):14–21.
10.
Baselga J, Mendelsohn J: Receptor blockade with monoclonal antibodies as anticancer therapy. Pharmacol Ther 1994;64:127–154.
11.
Baulida J, Kraus MH, Alimandi M, Di Fiore PP, Carpenter G: All ErbB receptors other than the epidermal growth factor receptor are endocytosis impaired. J Biol Chem 1996;271:5251–5257.
12.
Berchuck A, Kamel A, Whitaker R, Kerns B, Olt G, Kinney R, Soper JT, Dodge R, Clarke-Pearson DL, Marks P, et al: Overexpression of HER-2/neu is associated with poor survival in advanced epithelial ovarian cancer. Cancer Res 1990;50:4087–4091.
13.
Bertram J, Killian M, Brysch W, Schlingensiepen KH, Kneba M: Reduction of erbB2 gene product in mammary carcinoma cell lines by erbB2 mRNA specific and tyrosine kinase consensus phosphorothioate antisense oligonucleotides. Biochem Biophys Res Commun 1994;200:661–667.
14.
Burden S, Yarden Y: Neuregulins and their receptors: a versatile signaling module in organogenesis and oncogenesis. Neuron 1997;18:847–855.
15.
Carraway KL 3rd, Weber JL, Unger MJ, Ledesma J, Yu N, Gassmann M, Lai C: Neuregulin-2, a new ligand of erbB3/erbB4-receptor tyrosine kinases. Nature 1997;387:512–516.
16.
Carter P, Presta L, Gorman CM, Ridgway JB, Henner D, Wong WL, Rowland AM, Kotts C, Carver ME, Shepard HM: Humanization of the anti-p185HER2 antibody for human cancer therapy. Proc Natl Acad Sci USA 1992;89:4285–4289.
17.
Colomer R, Lupu R, Bacus SS, Gelmann EP: erbB-2 antisense oligonucleotides inhibit the proliferation of breast carcinoma cells with erbB-2 oncogene amplification. Br J Cancer 1994;70:819–825.
18.
Cooke T: What is HER2? Eur J Oncology Nursing 2000;4(suppl 1):2–9.
19.
Connelly PA, Stern DF: The epidermal growth factor receptor and the product of the neu-proto-oncogene are members of a receptor tyrosine phosphorylation cascade. Proc Natl Acad Sci USA 1990:87:6054–6057.
20.
Coussens L, Yang-Fen TL, Liao Y-C, Chen E, Gray A, McGrath J, Seeburg PH, Libermann TA, Schlessinger J, Francke U, Levinson A, Ullrich A: Tyrosine kinase receptor with extensive homology to EGF receptor shares chromosomal location with neu oncogene. Science 1985;230:1132–1139.
21.
De Potter CR, Schelfhout AM, Verbeek P, Lakhani SR, Brunken R, Schroeter CA, Van den Tweel JG, Schauer AJ, Sloane JP: Neu overexpression correlates with extent of disease in large cell ductal in situ carcinoma of the breast. Hum Pathol 1995;26:601–606.
22.
Devesa SS, Blot WJ, Stone BJ, Miller BA, Tarone RE, Fraumeni JF Jr: Recent cancer trends in the United States. J Natl Cancer Inst 1995;87:175–182.
23.
Di Augustine R, Richards RG: EGF-related peptides and their receptors in mammary gland development. Journal of Mammary Gland Biology and Neoplasia 1997;2:109–118.
24.
Drebin JA, Link VC, Stern DF, Weinberg RA, Greene MI: Down-modulation of an oncogene protein product and reversion of the transformed phenotype by monoclonal antibodies. Cell 1985;41:697–706.
25.
Drebin JA, Link VC, Greene MI: Monoclonal antibodies reactive with distinct domains of the neu oncogene-encoded p185 molecule exert synergistic anti-tumor effects in vivo. Oncogene 1988a;2:273–277.
26.
Drebin JA, Link VC, Greene MI: Monoclonal antibodies specific for the neu oncogene product directly mediate anti-tumor effects in vivo. Oncogene 1988b;2:387–394.
27.
Estéve J, Kricker A, Ferlay J, Parkin DM in collaboration with the Steering Committee of the European Network of Cancer Registries; in Facts and Figures of Cancer in the European Community. Paris, International Agency for Research on Cancer, 1996.
28.
Fendly BM, Winget M, Hudziak RM, Lipari MT, Napier MA, Ullrich A: Characterization of murine monoclonal antibodies reactive to either the human growth factor receptor or HER2/neu gene product. Cancer Res 1990;50:1550–1558.
29.
Guy PM, Platko JV, Cantley LC, Cerione RA, Carraway KL: Insect cell-expressed p180ErbB3 possesses an impaired tyrosine kinase activity. Proc Natl Acad Sci USA 1994;91:8132–8136.
30.
Hancock MC, Langton BC, Chan T, Toy P, Monahan JJ, Mischak RP, Shawver LK: A monoclonal antibody against the c-erbB-2 protein enhances the cytotoxicity of cis-diaminedichloroplatinum against human breast and ovarian tumor cell lines. Cancer Res 1991;51:4575–4580.
31.
Hou L, Shi D, Tu SM, Zhang HZ, Hung MC, Ling D: Oral cancer progression and c-erbB-2/neu proto-oncogene expression. Cancer Lett 1992;65:215–220.
32.
Hung MC, Lau Y-K: Basic science of HER2/neu: a review. Semin Oncol 1999;26:51–59.
33.
Hung MC, Schechter AL, Chevray PY, Stem DF, Weinberg RA: Molecular cloning of the neu gene: Absence of gross structural alteration in oncogenic alleles. Proc Natl Acad Sci USA 1986;83:261–264.
34.
Hurwitz E, Stancovski I, Sela M, Yarden Y: Suppression and promotion of tumor growth by monoclonal antibodies to ErbB-2 differentially correlate with cellular uptake. Proc Natl Acad Sci USA 1995;92:3353–3357.
35.
Hynes NE, Stern DF: The biology of erb B-2/neu/HER-2 and its role in cancer. Biochim Biophys Acta Rev Cancer 1994;1198:165–184.
36.
Jones FE, Jerry DJ, Guarino BC, Andrews GC, Stem DF: Heregulin induced in vivo proliferation and differentiation of mammary epithelium into secretory lobuloalveoli. Cell Growth Differ 1996;7:1031–1038.
37.
Karunagaren D, Tzahar E, Beerli RR, Chen X, Graus-Porta D, Ratzkin BJ, Seger R, Hynes NE, Yarden Y: ErbB-2 is a common auxiliary subunit of NDF and EGF receptors: implications for breast cancer. EMBO J 1996;15:254–264.
38.
Kasprzyk PG, Song SU, Di Fiore PP, King CR: Therapy of an animal model of human gastric cancer using a combination of anti-erbB-2 monoclonal antibodies. Cancer Res 1992;52:2771–2776.
39.
Klapper LN, Kirschbaum MH, Sela M, Yarden Y: Biochemical and clinical implications of the ErbB/HER signaling network of growth factor receptors; in Klein G, Woude V (eds): Advances in Cancer Research. Academic Press, 2000, pp 25–79.
40.
Klapper LN, Glathe S, Vaisman N, Hynes NE, Andrews GC, Sela M, Yarden Y: The ErbB-2/HER2 oncoprotein of human carcinomas may function solely as a shared coreceptor for multiple stroma-derived growth factors. Proc Natl Acad Sci USA 1999;96:4995–5000.
41.
Kokai Y, Meyers JN, Wada T, Brown VI, LeVea CM, Davis JG, Dobashi K, Greene MI: Synergistic interaction of p185c-neu and the EGF receptor leads to transformation of rodent fibroblasts. Cell 1989;58:287–292.
42.
Lenferink AE, Pinkas-Kramarski R, Van de Poll ML, Klapper LN, Tzahar E, Waterman H, Sela M, Van-Zoelen EY, Yarden Y: Differential endocytic routing of homo- and hetero-dimeric ErbB tyrosine kinases confers signaling superiority to receptor heterodimers. EMBO J 1998;17:3385–3397.
43.
Levkowitz G, Klapper LN, Tzahar E, Freywald A, Sela M, Yarden Y: Coupling of the c-Cbl proto-oncogene product to ErbB-1/EGF-receptor but not to other ErbB proteins. Oncogene 1996;12:1117–1125.
44.
Levkowitz G, Waterman H, Ettenberg SA, Katz M, Tsygankov AY, Alroy I, Lavi S, Iwai K, Reiss Y, Ciechenover A, Lipkowitz S, Yarden Y: Ubiquitin ligase activity and tyrosine phosphorylation underlie suppression of growth factor signaling by c-Cbl/Sli-1. Mol Cell 1999;4:1029–1040.
45.
Levkowitz G, Waterman H, Zamir L, Kam Z, Oved S, Langdon WY, Beguinot L, Geiger B, Yarden Y: c-Cbl/Sli-1 regulates endocytic sorting and ubiquitination of the epidermal growth factor receptor. Genes Dev 1998;12:3663–3674.
46.
Lupu R, Cardillo M, Harris L, Hijazi M, Rosenberg K: Interaction between ERB-receptors and heregulin in breast cancer tumor progression and drug resistance. Sem Cancer Biol 1995:6:135–145.
47.
McCann AH, Dervan PA, O’Regan M, Codd MB, Gullick WJ, Tobin BM, Carney DN: Prognostic significance of c-erbB-2 and estrogen receptor status in human breast cancer. Cancer Res 1991;51:3296–3303.
48.
Meyer C, Birchmeier C: Multiple essential functions of neuregulin in development. Nature 1995;378:386–390.
49.
Normanno N, Ciardiello F: EGF-related peptides in the pathophysiology of the mammary gland. J Mammary Gland Biol Neoplasia 1997;2:143–152.
50.
Pauletti G, Godolphin W, Press MF, Slamon DJ: Detection and quantitation of HER-2/neu gene amplification in human breast cancer archival material using fluorescence in situ hybridization. Oncogene 1996;13:63–72.
51.
Piccart M, Lohrisch C, Di Leo A, Larsimont D: The predictive value of HER2 in breast cancer. Oncology 2001;61(suppl 2):73–82.
52.
Pinkas-Kramarski R, Eilam R, Alroy I, Levkowitz G, Lonai P, Yarden Y: Differential expression of NDF/neuregulin receptors ErbB-3 and ErbB-4 and involvement in inhibition of neuronal differentiation. Oncogene 1997;15:803–815.
53.
Pinkas-Kramarski R, Shelly M, Guarino BC, Wang LM, Lyass L, Alroy I, Alimandi M, Kuo A, Moyer JD, Lavi S, Eisenstein M, Ratzkin BJ, Seger R, Bacus SS, Pierce JH, Andrews GC, Yarden Y, Alamandi M: ErbB tyrosine kinases and the two neuregulin families constitute a ligand-receptor network. Mol Cell Biol 1998;18:6090–6101.
54.
Pinkas-Kramarski R, Soussan L, Waterman H, Levkowitz G, Alroy I, Klapper L, Lavi S, Seger R, Ratzkin BJ, Sela M, Yarden Y: Diversification of Neu differentiation factor and epidermal growth factor signaling by combinatorial receptor interactions. EMBO J 1996;15:2452–2467.
55.
Quirke P, Pickles A, Tuzi NL, Mohamdee O, Gullick WJ: Pattern of expression of c-erbB-2 oncoprotein in human fetuses. Br J Cancer 1989;60:64–69.
56.
Ross JS, Fletcher JA: The Her-2/neu oncogene in breast cancer: prognostic factor, predictive factor, and target for therapy. Stem Cells 1998;16:413–428.
57.
Schneider PM, Hung MC, Chiocco SM, Manning J, Zhao XY, Fung K, Roth JA: Differential expression of the c-erbB-2 gene in human small cell and non-small cell lung cancer. Cancer Res 1989;49:4968–4971.
58.
Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL: Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 1987;235:177–182.
59.
Slamon DJ, Godolphin W, Jones LA, Holt JA, Wong SG, Keith DE, Levin WJ, Stuart SG, Udove J, Ullrich A, et al: Studies of the HER2/neu proto-oncogene in human and breast ovarian cancer. Science 1989;244:707–712.
60.
Sliwkowski MX, Schaefer G, Akita RW, Lofgren JA, Fitzpatrick VD, Nuijens A, Fendly BM, Cerione RA, Vandlen RL, Carraway KL: Co-expression of erbB2 and erbB3 proteins reconstitutes a high affinity receptor for heregulin. J Biol Chem 1994;269:14661–14665.
61.
Sliwkowski MX, Lofgren JA, Lewis GD, Hotaling TE, Fendly BM, Fox JA: Nonclinical studies addressing the mechanism of action of trastuzumab (Herceptin). Semin Oncol 1999;26:60–70.
62.
Stancovski I, Hurwitz E, Leitner O, Ullrich A, Yarden Y, Sela M: Mechanistic aspects of the opposing effects of monoclonal antibodies to the ERBB2 receptor on tumor growth. Proc Natl Acad Sci USA 1991;88:8691–8695.
63.
Thien CBF, Langdon W: c-Cbl: a regulator of T cell receptor-mediated signaling. Immunol Cell Biol 1998;76:473–82.
64.
Tzahar E, Pinkas-Kramarski R, Moyer JD, Klapper LN, Alroy I, Levkowitz G, Shelly M, Henis S, Eisenstein M, Ratzkin BJ, Sela M, Andrews GC, Yarden Y: Bivalence of EGF-like ligands drives the ErbB signaling network. EMBO J 1997;16:4938–4950.
65.
Tzahar E, Waterman H, Chen X, Levkowitz G, Karunagaran D, Lavi S, Ratzkin BJ, Yarden Y: A hierarchical network of interreceptor interactions determines signal transduction by Neu differentiation factor/neuregulin and epidermal growth factor. Mol Cell Biol 1996;16:5276–5287.
66.
Tzahar E, Yarden Y: The ErbB-2/HER2 oncogenic receptor of adenocarcinomas: from orphanhood to multiple stromal ligands. BBA Rev Cancer 1998;1377:25–37.
67.
van de Vijver M, van de Bersselaar R, Devilee P, Cornelisse C, Peterse J, Nusse R: Amplification of the neu/c-erbB-2 oncogene in human mammary tumors is relatively frequent and is often accompanied by amplification of the linked c-erbA oncogene. Mol Cell Biol 1987;7:2019–2023.
68.
van der Geer P, Hunter T, Lindberg RA: Receptor protein-tyrosine kinases and their signal transduction pathways. Annu Rev Cell Biol 1994;10:251–337.
69.
Vennstrom B, Bishop JM: Isolation and characterization of chicken DNA homologous to the two putative oncogenes of avian erythroblastosis virus. Cell 1982;28:135–143.
70.
Venter DJ, Tuzi NL, Kumar S, Gullick WJ: Overexpression of the c-erbB-2 oncoprotein in human breast carcinomas: immunohistological assessment correlates with gene amplification. Lancet 1987;ii:69–72.
71.
Waterman H, Alroy I, Strano S, Seger R, Yarden Y: The carboxyl terminus of the kinase-defective neuregulin receptor ErbB-3 confers mitogenic superiority and dictates endocytic routing. EMBO J 1999;18:3348–3358.
72.
Waterman H, Sabanai I, Geiger B, Yarden Y: Alternative intracellular routing of ErbB receptors may determine signaling potency. J Biol Chem 1998;273:13819–13827.
73.
Weiner DB, Nordberg J, Robinson R, Nowell PC, Gazdar A, Greene MI, Williams WV, Cohen JA, Kern JA: Expression of the neu gene-encoded protein (P185neu) in human non-small cell carcinomas of the lung. Cancer Res 1990;50:421–425.
74.
Xia W, Lau Y-K, Zhang H-Z, Liu AR, Li L, Kiyokawa N, Clayman GL, Katz RL, Hung MC: Strong correlation between c-erbB-2 overexpression and overall survival of patients with oral squamous cell carcinoma. Clin Cancer Res 1997;3:3–9.
75.
Yamamoto T, Ikawa S, Akiyama T, Semba K, Nomura N, Miyajima N, Saito T, Toyoshima K: Similarity of protein encoded by the human c-erb-2 gene to epidermal growth factor receptor. Nature 1986;319:230–234.
76.
Yang T, Spitzer E, Meyer D, Sachs M, Niemann C, Hartman G, Weidner KM, Birchmeier C, Birchmeier W: Sequential requirement of hepatocyte growth factor and neuregulin in the morphogenesis and differentiation of the mammary gland. J Cell Biol 1995;131:215–226.
77.
Yokota J, Yamamoto T, Miyajima N, Toyoshima K, Nomura N, Sakamoto H, Yoshida T, Terada M, Sugimura T: Genetic alterations of the c-erbB-2 oncogene occur frequently in tubular adenocarcinoma of the stomach and are often accompanied by amplification of the v-erbA homologue. Oncogene 1988;2:283–287.
78.
Yoshida K, Tsuda T, Matsumura T, Tsujino T, Hattori T, Ito H, Tahara E: Amplification of epidermal growth factor receptor (EGFR) gene and oncogenes in human gastric carcinomas. Virchows Arch B Cell Pathol Mol Pathol 1989;57:285–290.
79.
Zhang X, Silva E, Gersenhson D, Hung MC: Amplification and re-arrangement of c-erbB proto-oncogenes in cancer of human female genital tract. Oncogene 1989;4:985–989.
80.
Zheng EF, Kuduk SD, Chiosis G, Munster PN, Sepp-Lorenzino L, Danishefsky SJ, Rosen N: Identification of a geldanamycin dimer that induces selective degradation of HER-family tyrosine kinases. Cancer Res 2000;60:2090–2094.
© 2001 S. Karger AG, Basel
2001
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.