Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

The oncogene HER2: its signaling and transforming functions and its role in human cancer pathogenesis

Abstract

The year 2007 marks exactly two decades since Human Epidermal Growth Factor Receptor-2 (HER2) was functionally implicated in the pathogenesis of human breast cancer. This finding established the HER2 oncogene hypothesis for the development of some human cancers. The subsequent two decades have brought about an explosion of information about the biology of HER2 and the HER family. An abundance of experimental evidence now solidly supports the HER2 oncogene hypothesis and etiologically links amplification of the HER2 gene locus with human cancer pathogenesis. The molecular mechanisms underlying HER2 tumorigenesis appear to be complex and a unified mechanistic model of HER2-induced transformation has not emerged. Numerous hypotheses implicating diverse transforming pathways have been proposed and are individually supported by experimental models and HER2 may indeed induce cell transformation through multiple mechanisms. Here I review the evidence supporting the oncogenic function of HER2, the mechanisms that are felt to mediate its oncogenic functions, and the evidence that links the experimental evidence with human cancer pathogenesis.

This is a preview of subscription content

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1
Figure 2
Figure 3
Figure 4

References

  • Ahnstrom M, Nordenskjold B, Rutqvist LE, Skoog L, Stal O . (2005). Role of cyclin D1 in ErbB2-positive breast cancer and tamoxifen resistance. Breast Cancer Res Treat 91: 145–151.

    Article  CAS  PubMed  Google Scholar 

  • Akiyama T, Sudo C, Ogawara H, Toyoshima K, Yamamoto T . (1986). The product of the human c-erbB-2 gene: a 185-kilodalton glycoprotein with tyrosine kinase activity. Science 232: 1644–1646.

    Article  CAS  PubMed  Google Scholar 

  • Alimandi M, Romano A, Curia MC, Muraro R, Fedi P, Aaronson SA et al. (1995). Cooperative signaling of ErbB3 and ErbB2 in neoplastic transformation and human mammary carcinomas. Oncogene 10: 1813–1821.

    CAS  PubMed  Google Scholar 

  • Alpy F, Tomasetto C . (2006). MLN64 and MENTHO, two mediators of endosomal cholesterol transport. Biochem Soc Trans 34: 343–345.

    Article  CAS  PubMed  Google Scholar 

  • Amundadottir LT, Leder P . (1998). Signal transduction pathways activated and required for mammary carcinogenesis in response to specific oncogenes. Oncogene 16: 737–746.

    Article  CAS  PubMed  Google Scholar 

  • Andrechek ER, Hardy WR, Siegel PM, Rudnicki MA, Cardiff RD, Muller WJ . (2000). Amplification of the neu/erbB-2 oncogene in a mouse model of mammary tumorigenesis. Proc Natl Acad Sci USA 97: 3444–3449.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Andrechek ER, White D, Muller WJ . (2005). Targeted disruption of ErbB2/Neu in the mammary epithelium results in impaired ductal outgrowth. Oncogene 24: 932–937.

    Article  CAS  PubMed  Google Scholar 

  • Aranda V, Haire T, Nolan ME, Calarco JP, Rosenberg AZ, Fawcett JP et al. (2006). Par6-aPKC uncouples ErbB2 induced disruption of polarized epithelial organization from proliferation control. Nat Cell Biol 8: 1235–1245.

    Article  CAS  PubMed  Google Scholar 

  • Baasner S, von MH, Klenner T, Hilgard P, Beckers T . (1996). Reversible tumorigenesis in mice by conditional expression of the HER2/c-erbB2 receptor tyrosine kinase. Oncogene 13: 901–911.

    CAS  PubMed  Google Scholar 

  • Bargmann CI, Hung MC, Weinberg RA . (1986). Multiple independent activations of the neu oncogene by a point mutation altering the transmembrane domain of p185. Cell 45: 649–657.

    Article  CAS  PubMed  Google Scholar 

  • Barnes CJ, Kumar R . (2004). Biology of the epidermal growth factor receptor family. Cancer Treat Res 119: 1–13.

    Article  CAS  PubMed  Google Scholar 

  • Baulida J, Kraus MH, Alimandi M, Di Fiore PP, Carpenter G . (1996). All ErbB receptors other than the epidermal growth factor receptor are endocytosis impaired. J Biol Chem 271: 5251–5257.

    Article  CAS  PubMed  Google Scholar 

  • Bazley LA, Gullick WJ . (2005). The epidermal growth factor receptor family. Endocr Relat Cancer 12 (Suppl 1): S17–S27.

    Article  CAS  PubMed  Google Scholar 

  • Beerli RR, Wels W, Hynes NE . (1994). Intracellular expression of single chain antibodies reverts ErbB-2 transformation. J Biol Chem 269: 23931–23936.

    CAS  PubMed  Google Scholar 

  • Belsches-Jablonski AP, Biscardi JS, Peavy DR, Tice DA, Romney DA, Parsons SJ . (2001). Src family kinases and HER2 interactions in human breast cancer cell growth and survival. Oncogene 20: 1465–1475.

    Article  CAS  PubMed  Google Scholar 

  • Benlimame N, He Q, Jie S, Xiao D, Xu YJ, Loignon M et al. (2005). FAK signaling is critical for ErbB-2/ErbB-3 receptor cooperation for oncogenic transformation and invasion. J Cell Biol 171: 505–516.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Benusiglio PR, Lesueur F, Luccarini C, Conroy DM, Shah M, Easton DF et al. (2005). Common ERBB2 polymorphisms and risk of breast cancer in a white British population: a case-control study. Breast Cancer Res 7: R204–R209.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Benz CC, Scott GK, Sarup JC, Johnson RM, Tripathy D, Coronado E et al. (1992). Estrogen-dependent, tamoxifen-resistant tumorigenic growth of MCF-7 cells transfected with HER2/neu. Breast Cancer Res Treat 24: 85–95.

    Article  CAS  PubMed  Google Scholar 

  • Berger MB, Mendrola JM, Lemmon MA . (2004). ErbB3/HER3 does not homodimerize upon neuregulin binding at the cell surface. FEBS Lett 569: 332–336.

    Article  CAS  PubMed  Google Scholar 

  • Bol D, Kiguchi K, Beltran L, Rupp T, Moats S, Gimenez-Conti I et al. (1998). Severe follicular hyperplasia and spontaneous papilloma formation in transgenic mice expressing the neu oncogene under the control of the bovine keratin 5 promoter. Mol Carcinog 21: 2–12.

    Article  CAS  PubMed  Google Scholar 

  • Borg JP, Marchetto S, Le BA, Ollendorff V, Jaulin-Bastard F, Saito H et al. (2000). ERBIN: a basolateral PDZ protein that interacts with the mammalian ERBB2/HER2 receptor. Nat Cell Biol 2: 407–414.

    Article  CAS  PubMed  Google Scholar 

  • Bouchard L, Lamarre L, Tremblay PJ, Jolicoeur P . (1989). Stochastic appearance of mammary tumors in transgenic mice carrying the MMTV/c-neu oncogene. Cell 57: 931–936.

    Article  CAS  PubMed  Google Scholar 

  • Bowe DB, Kenney NJ, Adereth Y, Maroulakou IG . (2002). Suppression of Neu-induced mammary tumor growth in cyclin D1 deficient mice is compensated for by cyclin E. Oncogene 21: 291–298.

    Article  CAS  PubMed  Google Scholar 

  • Brandt R, Wong AM, Hynes NE . (2001). Mammary glands reconstituted with Neu/ErbB2 transformed HC11 cells provide a novel orthotopic tumor model for testing anti-cancer agents. Oncogene 20: 5459–5465.

    Article  CAS  PubMed  Google Scholar 

  • Britsch S, Li L, Kirchhoff S, Theuring F, Brinkmann V, Birchmeier C et al. (1998). The ErbB2 and ErbB3 receptors and their ligand, neuregulin-1, are essential for development of the sympathetic nervous system. Genes Dev 12: 1825–1836.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Burgess AW, Cho HS, Eigenbrot C, Ferguson KM, Garrett TP, Leahy DJ et al. (2003). An open-and-shut case? Recent insights into the activation of EGF/ErbB receptors. Mol Cell 12: 541–552.

    Article  CAS  PubMed  Google Scholar 

  • Carlsson J, Nordgren H, Sjostrom J, Wester K, Villman K, Bengtsson NO et al. (2004). HER2 expression in breast cancer primary tumours and corresponding metastases. Original data and literature review. Br J Cancer 90: 2344–2348.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Carraway III KL, Rossi EA, Komatsu M, Price-Schiavi SA, Huang D, Guy PM et al. (1999). An intramembrane modulator of the ErbB2 receptor tyrosine kinase that potentiates neuregulin signaling. J Biol Chem 274: 5263–5266.

    Article  CAS  PubMed  Google Scholar 

  • Castiglioni F, Tagliabue E, Campiglio M, Pupa SM, Balsari A, Menard S . (2006). Role of exon-16-deleted HER2 in breast carcinomas. Endocr Relat Cancer 13: 221–232.

    Article  CAS  PubMed  Google Scholar 

  • Chazin VR, Kaleko M, Miller AD, Slamon DJ . (1992). Transformation mediated by the human HER-2 gene independent of the epidermal growth factor receptor. Oncogene 7: 1859–1866.

    CAS  PubMed  Google Scholar 

  • Cho HS, Mason K, Ramyar KX, Stanley AM, Gabelli SB, Denney Jr DW et al. (2003). Structure of the extracellular region of HER2 alone and in complex with the Herceptin Fab. Nature 421: 756–760.

    Article  CAS  PubMed  Google Scholar 

  • Choudhury A, Charo J, Parapuram SK, Hunt RC, Hunt DM, Seliger B et al. (2004). Small interfering RNA (siRNA) inhibits the expression of the Her2/neu gene, upregulates HLA class I and induces apoptosis of Her2/neu positive tumor cell lines. Int J Cancer 108: 71–77.

    Article  CAS  PubMed  Google Scholar 

  • Colomer R, Lupu R, Bacus SS, Gelmann EP . (1994). erbB-2 antisense oligonucleotides inhibit the proliferation of breast carcinoma cells with erbB-2 oncogene amplification. Br J Cancer 70: 819–825.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cool M, Jolicoeur P . (1999). Elevated frequency of loss of heterozygosity in mammary tumors arising in mouse mammary tumor virus/neu transgenic mice. Cancer Res 59: 2438–2444.

    CAS  PubMed  Google Scholar 

  • Crowe JP, Patrick RJ, Rybicki LA, Escobar PF, Weng D, Thomas BG et al. (2006). A data model to predict HER2 status in breast cancer based on the clinical and pathologic profiles of a large patient population at a single institution. Breast 15: 728–735.

    Article  PubMed  Google Scholar 

  • De Potter CR, Quatacker J, Maertens G, Van DS, Pauwels C, Verhofstede C et al. (1989). The subcellular localization of the neu protein in human normal and neoplastic cells. Int J Cancer 44: 969–974.

    Article  CAS  PubMed  Google Scholar 

  • Deshane J, Grim J, Loechel S, Siegal GP, Alvarez RD, Curiel DT . (1996). Intracellular antibody against erbB-2 mediates targeted tumor cell eradication by apoptosis. Cancer Gene Ther 3: 89–98.

    CAS  PubMed  Google Scholar 

  • Di Fiore PP, Pierce JH, Kraus MH, Segatto O, King CR, Aaronson SA . (1987). erbB-2 is a potent oncogene when overexpressed in NIH/3T3 cells. Science 237: 178–182.

    Article  CAS  PubMed  Google Scholar 

  • Donovan JC, Milic A, Slingerland JM . (2001). Constitutive MEK/MAPK activation leads to p27(Kip1) deregulation and antiestrogen resistance in human breast cancer cells. J Biol Chem 276: 40888–40895.

    Article  CAS  PubMed  Google Scholar 

  • Erickson SL, O’Shea KS, Ghaboosi N, Loverro L, Frantz G, Bauer M et al. (1997). ErbB3 is required for normal cerebellar and cardiac development: a comparison with ErbB2-and heregulin-deficient mice. Development 124: 4999–5011.

    CAS  PubMed  Google Scholar 

  • Falcioni R, Antonini A, Nistico P, Di SS, Crescenzi M, Natali PG et al. (1997). 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.

    Article  CAS  PubMed  Google Scholar 

  • Faltus T, Yuan J, Zimmer B, Kramer A, Loibl S, Kaufmann M et al. (2004). Silencing of the HER2/neu gene by siRNA inhibits proliferation and induces apoptosis in HER2/neu-overexpressing breast cancer cells. Neoplasia 6: 786–795.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fedi P, Pierce JH, Di Fiore PP, Kraus MH . (1994). Efficient coupling with phosphatidylinositol 3-kinase, but not phospholipase C gamma or GTPase-activating protein, distinguishes ErbB-3 signaling from that of other ErbB/EGFR family members. Mol Cell Biol 14: 492–500.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Finkle D, Quan ZR, Asghari V, Kloss J, Ghaboosi N, Mai E et al. (2004). HER2-targeted therapy reduces incidence and progression of midlife mammary tumors in female murine mammary tumor virus huHER2-transgenic mice. Clin Cancer Res 10: 2499–2511.

    Article  CAS  PubMed  Google Scholar 

  • Fleishman SJ, Schlessinger J, Ben-Tal N . (2002). A putative molecular-activation switch in the transmembrane domain of erbB2. Proc Natl Acad Sci USA 99: 15937–15940.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Funes M, Miller JK, Lai C, Carraway III KL, Sweeney C . (2006). The mucin Muc4 potentiates neuregulin signaling by increasing the cell surface populations of ErbB2 and ErbB3. J Biol Chem.

  • Gabos Z, Sinha R, Hanson J, Chauhan N, Hugh J, Mackey JR et al. (2006). Prognostic significance of human epidermal growth factor receptor positivity for the development of brain metastasis after newly diagnosed breast cancer. J Clin Oncol 24: 5658–5663.

    Article  CAS  PubMed  Google Scholar 

  • Gambaletta D, Marchetti A, Benedetti L, Mercurio AM, Sacchi A, Falcioni R . (2000). Cooperative signaling between alpha(6)beta(4) integrin and ErbB-2 receptor is required to promote phosphatidylinositol 3-kinase-dependent invasion. J Biol Chem 275: 10604–10610.

    Article  CAS  PubMed  Google Scholar 

  • Garrett TP, McKern NM, Lou M, Elleman TC, Adams TE, Lovrecz GO et al. (2003). The crystal structure of a truncated ErbB2 ectodomain reveals an active conformation, poised to interact with other ErbB receptors. Mol Cell 11: 495–505.

    Article  CAS  PubMed  Google Scholar 

  • Gassmann M, Casagranda F, Orioli D, Simon H, Lai C, Klein R et al. (1995). Aberrant neural and cardiac development in mice lacking the ErbB4 neuregulin receptor. (see comment). Nature 378: 390–394.

    Article  CAS  PubMed  Google Scholar 

  • Goel A, Janknecht R . (2003). Acetylation-mediated transcriptional activation of the ETS protein ER81 by p300, P/CAF, and HER2/Neu. Mol Cell Biol 23: 6243–6254.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Goodearl A, Viehover A, Vartanian T . (2001). Neuregulin-induced association of Sos Ras exchange protein with HER2(erbB2)/HER3(erbB3) receptor complexes in Schwann cells through a specific Grb2-HER2(erbB2) interaction. Dev Neurosci 23: 25–30.

    Article  CAS  PubMed  Google Scholar 

  • Goueli BS, Janknecht R . (2004). Upregulation of the catalytic telomerase subunit by the transcription factor ER81 and oncogenic HER2/Neu, Ras, or Raf. Mol Cell Biol 24: 25–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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: 1647–1655.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Guo W, Pylayeva Y, Pepe A, Yoshioka T, Muller WJ, Inghirami G et al. (2006). Beta 4 integrin amplifies ErbB2 signaling to promote mammary tumorigenesis. Cell 126: 489–502.

    Article  CAS  PubMed  Google Scholar 

  • Guy CT, Webster MA, Schaller M, Parsons TJ, Cardiff RD, Muller WJ . (1992). Expression of the neu protooncogene in the mammary epithelium of transgenic mice induces metastatic disease. Proc Natl Acad Sci USA 89: 10578–10582.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hellyer NJ, Kim MS, Koland JG . (2001). Heregulin-dependent activation of phosphoinositide 3-kinase and Akt via the ErbB2/ErbB3 co-receptor. J Biol Chem 276: 42153–42161.

    Article  CAS  PubMed  Google Scholar 

  • Hendriks BS, Opresko LK, Wiley HS, Lauffenburger D . (2003a). Quantitative analysis of HER2-mediated effects on HER2 and epidermal growth factor receptor endocytosis: distribution of homo- and heterodimers depends on relative HER2 levels. J Biol Chem 278: 23343–23351.

    Article  CAS  PubMed  Google Scholar 

  • Hendriks BS, Wiley HS, Lauffenburger D . (2003b). HER2-mediated effects on EGFR endosomal sorting: analysis of biophysical mechanisms. Biophys J 85: 2732–2745.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hicks DG, Tubbs RR . (2005). Assessment of the HER2 status in breast cancer by fluorescence in situ hybridization: a technical review with interpretive guidelines. Hum Pathol 36: 250–261.

    Article  CAS  PubMed  Google Scholar 

  • Hirsch FR, Varella-Garcia M, Franklin WA, Veve R, Chen L, Helfrich B et al. (2002). Evaluation of HER-2/neu gene amplification and protein expression in non-small cell lung carcinomas. Br J Cancer 86: 1449–1456.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hodgson JG, Malek T, Bornstein S, Hariono S, Ginzinger DG, Muller WJ et al. (2005). Copy number aberrations in mouse breast tumors reveal loci and genes important in tumorigenic receptor tyrosine kinase signaling. Cancer Res 65: 9695–9704.

    Article  CAS  PubMed  Google Scholar 

  • Holbro T, Beerli RR, Maurer F, Koziczak M, Barbas III CF, Hynes NE . (2003). The ErbB2/ErbB3 heterodimer functions as an oncogenic unit: ErbB2 requires ErbB3 to drive breast tumor cell proliferation. Proc Natl Acad Sci USA 100: 8933–8938.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Horan T, Wen J, Arakawa T, Liu N, Brankow D, Hu S et al. (1995). Binding of Neu differentiation factor with the extracellular domain of Her2 and Her3. J Biol Chem 270: 24604–24608.

    Article  CAS  PubMed  Google Scholar 

  • Howe LR, Chang SH, Tolle KC, Dillon R, Young LJ, Cardiff RD et al. (2005). HER2/neu-induced mammary tumorigenesis and angiogenesis are reduced in cyclooxygenase-2 knockout mice. Cancer Res 65: 10113–10119.

    Article  CAS  PubMed  Google Scholar 

  • Huang G, Chantry A, Epstein RJ . (1999). Overexpression of ErbB2 impairs ligand-dependent downregulation of epidermal growth factor receptors via a post-transcriptional mechanism. J Cell Biochem 74: 23–30.

    Article  CAS  PubMed  Google Scholar 

  • Hudziak RM, Schlessinger J, Ullrich A . (1987). Increased expression of the putative growth factor receptor p185HER2 causes transformation and tumorigenesis of NIH 3T3 cells. Proc Natl Acad Sci USA 84: 7159–7163.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hynes NE, Lane HA . (2001). Myc and mammary cancer: Myc is a downstream effector of the ErbB2 receptor tyrosine kinase. J Mammary Gland Biol Neoplasia 6: 141–150.

    Article  CAS  PubMed  Google Scholar 

  • Ignatoski KM, Maehama T, Markwart SM, Dixon JE, Livant DL, Ethier SP . (2000). ERBB-2 overexpression confers PI 3′ kinase-dependent invasion capacity on human mammary epithelial cells. Br J Cancer 82: 666–674.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ishizawar RC, Miyake T, Parsons SJ . (2006). c-Src modulates ErbB2 and ErbB3 heterocomplex formation and function. Oncogene Advance online publication; doi: 10.1038/sj.onc.1210138.

  • Isola J, Chu L, DeVries S, Matsumura K, Chew K, Ljung BM et al. (1999). Genetic alterations in ERBB2-amplified breast carcinomas. Clin Cancer Res 5: 4140–4145.

    CAS  PubMed  Google Scholar 

  • Janes PW, Lackmann M, Church WB, Sanderson GM, Sutherland RL, Daly RJ . (1997). Structural determinants of the interaction between the erbB2 receptor and the Src homology 2 domain of Grb7. J Biol Chem 272: 8490–8497.

    Article  CAS  PubMed  Google Scholar 

  • Juhl H, Downing SG, Wellstein A, Czubayko F . (1997). HER-2/neu is rate-limiting for ovarian cancer growth. Conditional depletion of HER-2/neu by ribozyme targeting. J Biol Chem 272: 29482–29486.

    Article  CAS  PubMed  Google Scholar 

  • Kallioniemi OP, Kallioniemi A, Kurisu W, Thor A, Chen LC, Smith HS et al. (1992). ERBB2 amplification in breast cancer analyzed by fluorescence in situ hybridization. Proc Natl Acad Sci USA 89: 5321–5325.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Karunagaran D, Tzahar E, Beerli RR, Chen X, Graus-Porta D, Ratzkin BJ et al. (1996). ErbB-2 is a common auxiliary subunit of NDF and EGF receptors: implications for breast cancer. EMBO J 15: 254–264.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kauraniemi P, Barlund M, Monni O, Kallioniemi A . (2001). New amplified and highly expressed genes discovered in the ERBB2 amplicon in breast cancer by cDNA microarrays. Cancer Res 61: 8235–8240.

    CAS  PubMed  Google Scholar 

  • Kauraniemi P, Kallioniemi A . (2006). Activation of multiple cancer-associated genes at the ERBB2 amplicon in breast cancer. Endocr Relat Cancer 13: 39–49.

    Article  CAS  PubMed  Google Scholar 

  • Kauraniemi P, Kuukasjarvi T, Sauter G, Kallioniemi A . (2003). Amplification of a 280-kilobase core region at the ERBB2 locus leads to activation of two hypothetical proteins in breast cancer. Am J Pathol 163: 1979–1984.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Keely SJ, Barrett KE . (1999). ErbB2 and ErbB3 receptors mediate inhibition of calcium-dependent chloride secretion in colonic epithelial cells. J Biol Chem 274: 33449–33454.

    Article  CAS  PubMed  Google Scholar 

  • Khan AJ, King BL, Smith BD, Smith GL, DiGiovanna MP, Carter D et al. (2002). Characterization of the HER-2/neu oncogene by immunohistochemical and fluorescence in situ hybridization analysis in oral and oropharyngeal squamous cell carcinoma. Clin Cancer Res 8: 540–548.

    CAS  PubMed  Google Scholar 

  • Kiguchi K, Bol D, Carbajal S, Beltran L, Moats S, Chan K et al. (2000). Constitutive expression of erbB2 in epidermis of transgenic mice results in epidermal hyperproliferation and spontaneous skin tumor development. Oncogene 19: 4243–4254.

    Article  CAS  PubMed  Google Scholar 

  • Kiguchi K, Carbajal S, Chan K, Beltran L, Ruffino L, Shen J et al. (2001). Constitutive expression of ErbB-2 in gallbladder epithelium results in development of adenocarcinoma. Cancer Res 61: 6971–6976.

    CAS  PubMed  Google Scholar 

  • Kim H, Chan R, Dankort DL, Zuo D, Najoukas M, Park M et al. (2005). The c-Src tyrosine kinase associates with the catalytic domain of ErbB-2: implications for ErbB-2 mediated signaling and transformation. Oncogene 24: 7599–7607.

    Article  CAS  PubMed  Google Scholar 

  • Kim HH, Vijapurkar U, Hellyer NJ, Bravo D, Koland JG . (1998). Signal transduction by epidermal growth factor and heregulin via the kinase-deficient ErbB3 protein. Biochem J 334: 189–195.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • King CR, Kraus MH, Aaronson SA . (1985). Amplification of a novel v-erbB-related gene in a human mammary carcinoma. Science 229: 974–976.

    Article  CAS  PubMed  Google Scholar 

  • Kraus MH, Issing W, Miki T, Popescu NC, Aaronson SA . (1989). 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Lacenere CJ, Sternberg PW . (2000). Regulation of EGF receptor signaling in the fruitfly D. melanogaster and the nematode C. elegans. Breast Dis 11: 19–30.

    Article  CAS  PubMed  Google Scholar 

  • Latif Z, Watters AD, Dunn I, Grigor KM, Underwood MA, Bartlett JM . (2003). HER2/neu overexpression in the development of muscle-invasive transitional cell carcinoma of the bladder. Br J Cancer 89: 1305–1309.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Latta EK, Tjan S, Parkes RK, O’Malley FP . (2002). The role of HER2/neu overexpression/amplification in the progression of ductal carcinoma in situ to invasive carcinoma of the breast. Mod Pathol 15: 1318–1325.

    Article  CAS  PubMed  Google Scholar 

  • Laughner E, Taghavi P, Chiles K, Mahon PC, Semenza GL . (2001). HER2 (neu) signaling increases the rate of hypoxia-inducible factor 1alpha (HIF-1alpha) synthesis: novel mechanism for HIF-1-mediated vascular endothelial growth factor expression. Mol Cell Biol 21: 3995–4004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee JW, Soung YH, Seo SH, Kim SY, Park CH, Wang YP et al. (2006). Somatic mutations of ERBB2 kinase domain in gastric, colorectal, and breast carcinomas. Clin Cancer Res 12: 57–61.

    Article  CAS  PubMed  Google Scholar 

  • Lee KF, Simon H, Chen H, Bates B, Hung MC, Hauser C . (1995). Requirement for neuregulin receptor erbB2 in neural and cardiac development. (see comment). Nature 378: 394–398.

    Article  CAS  PubMed  Google Scholar 

  • Lee RJ, Albanese C, Fu M, D’Amico M, Lin B, Watanabe G et al. (2000). Cyclin D1 is required for transformation by activated Neu and is induced through an E2F-dependent signaling pathway. Mol Cell Biol 20: 672–683.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lemoine NR, Barnes DM, Hollywood DP, Hughes CM, Smith P, Dublin E et al. (1992). Expression of the ERBB3 gene product in breast cancer. Br J Cancer 66: 1116–1121.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lenferink AE, Busse D, Flanagan WM, Yakes FM, Arteaga CL . (2001). ErbB2/neu kinase modulates cellular p27(Kip1) and cyclin D1 through multiple signaling pathways. Cancer Res 61: 6583–6591.

    CAS  PubMed  Google Scholar 

  • Lenferink AE, Pinkas-Kramarski R, van de Poll ML, van Vugt MJ, Klapper LN, Tzahar E et al. (1998). Differential endocytic routing of homo- and hetero-dimeric ErbB tyrosine kinases confers signaling superiority to receptor heterodimers. EMBO J 17: 3385–3397.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li B, Rosen JM, Menamin-Balano J, Muller WJ, Perkins AS . (1997). neu/ERBB2 cooperates with p53-172H during mammary tumorigenesis in transgenic mice. Mol Cell Biol 17: 3155–3163.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li YM, Pan Y, Wei Y, Cheng X, Zhou BP, Tan M et al. (2004). Upregulation of CXCR4 is essential for HER2-mediated tumor metastasis. Cancer Cell 6: 459–469.

    Article  CAS  PubMed  Google Scholar 

  • Li YM, Zhou BP, Deng J, Pan Y, Hay N, Hung MC . (2005). A hypoxia-independent hypoxia-inducible factor-1 activation pathway induced by phosphatidylinositol-3 kinase/Akt in HER2 overexpressing cells. Cancer Res 65: 3257–3263.

    Article  CAS  PubMed  Google Scholar 

  • Li Z, Szabolcs M, Terwilliger JD, Efstratiadis A . (2006). Prostatic intraepithelial neoplasia and adenocarcinoma in mice expressing a probasin-Neu oncogenic transgene. Carcinogenesis 27: 1054–1067.

    Article  CAS  PubMed  Google Scholar 

  • Liang J, Zubovitz J, Petrocelli T, Kotchetkov R, Connor MK, Han K et al. (2002). PKB/Akt phosphorylates p27, impairs nuclear import of p27 and opposes p27-mediated G1 arrest. Nat Med 8: 1153–1160.

    Article  CAS  PubMed  Google Scholar 

  • Liu E, Thor A, He M, Barcos M, Ljung BM, Benz C . (1992). The HER2 (c-erbB-2) oncogene is frequently amplified in in situ carcinomas of the breast. Oncogene 7: 1027–1032.

    CAS  PubMed  Google Scholar 

  • Loden M, Perris F, Nielsen NH, Emdin SO, Landberg G . (2003). C-erbB2, p27 and G1/S aberrations in human primary breast cancer. Anticancer Res 23: 2053–2061.

    CAS  PubMed  Google Scholar 

  • Lohrisch C, Piccart M . (2001). An overview of HER2. Semin Oncol 28: 3–11.

    Article  CAS  PubMed  Google Scholar 

  • Loureiro RM, Maharaj AS, Dankort D, Muller WJ, D’Amore PA . (2005). ErbB2 overexpression in mammary cells upregulates VEGF through the core promoter. Biochem Biophys Res Commun 326: 455–465.

    Article  CAS  PubMed  Google Scholar 

  • Luo J, Manning BD, Cantley LC . (2003). Targeting the PI3K-Akt pathway in human cancer: rationale and promise. Cancer Cell 4: 257–262.

    Article  CAS  PubMed  Google Scholar 

  • Luoh SW . (2002). Amplification and expression of genes from the 17q11 approximately q12 amplicon in breast cancer cells. Cancer Genet Cytogenet 136: 43–47.

    Article  CAS  PubMed  Google Scholar 

  • Makino K, Day CP, Wang SC, Li YM, Hung MC . (2004). Upregulation of IKKalpha/IKKbeta by integrin-linked kinase is required for HER2/neu-induced NF-kappaB antiapoptotic pathway. Oncogene 23: 3883–3887.

    Article  CAS  PubMed  Google Scholar 

  • Manning G, Whyte DB, Martinez R, Hunter T, Sudarsanam S . (2002). The protein kinase complement of the human genome. Science 298: 1912–1934.

    Article  CAS  PubMed  Google Scholar 

  • Mano MS, Rosa DD, De Azambuja E, Ismael GFV, Durbecq V . (2006). The 17q12-q21 amplicon: Her2 and topoisomerase-II[alpha] and their importance to the biology of solid tumours. Cancer Treat Rev 33: 64–77.

    Article  CAS  PubMed  Google Scholar 

  • Mendelsohn J, Baselga J . (2000). The EGF receptor family as targets for cancer therapy. Oncogene 19: 6550–6565.

    Article  CAS  PubMed  Google Scholar 

  • Messerle K, Schlegel J, Hynes NE, Groner B . (1994). NIH/3T3 cells transformed with the activated erbB-2 oncogene can be phenotypically reverted by a kinase deficient, dominant negative erbB-2 variant. Mol Cell Endocrinol 105: 1–10.

    Article  CAS  PubMed  Google Scholar 

  • Miettinen PJ, Berger JE, Meneses J, Phung Y, Pedersen RA, Werb Z et al. (1995). Epithelial immaturity and multiorgan failure in mice lacking epidermal growth factor receptor. Nature, 337–341.

  • Mimura K, Kono K, Hanawa M, Mitsui F, Sugai H, Miyagawa N et al. (2005). Frequencies of HER-2/neu expression and gene amplification in patients with oesophageal squamous cell carcinoma. Br J Cancer 92: 1253–1260.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Moghal N, Sternberg PW . (2003). The epidermal growth factor system in Caenorhabditis elegans. Exp Cell Res 284: 150–159.

    Article  CAS  PubMed  Google Scholar 

  • Montgomery KG, Gertig DM, Baxter SW, Milne RL, Dite GS, McCredie MR et al. (2003). The HER2 I655V polymorphism and risk of breast cancer in women < age 40 years. Cancer Epidemiol Biomarkers Prev 12: 1109–1111.

    CAS  PubMed  Google Scholar 

  • Moody SE, Sarkisian CJ, Hahn KT, Gunther EJ, Pickup S, Dugan KD et al. (2002). Conditional activation of Neu in the mammary epithelium of transgenic mice results in reversible pulmonary metastasis. Cancer Cell 2: 451–461.

    Article  CAS  PubMed  Google Scholar 

  • Morris JK, Lin W, Hauser C, Marchuk Y, Getman D, Lee KF . (1999). Rescue of the cardiac defect in ErbB2 mutant mice reveals essential roles of ErbB2 in peripheral nervous system development. Neuron 23: 273–283.

    Article  CAS  PubMed  Google Scholar 

  • Morrison C, Zanagnolo V, Ramirez N, Cohn DE, Kelbick N, Copeland L et al. (2006). HER-2 is an independent prognostic factor in endometrial cancer: association with outcome in a large cohort of surgically staged patients. J Clin Onc 24: 2376–2385.

    Article  CAS  Google Scholar 

  • Muller A, Homey B, Soto H, Ge N, Catron D, Buchanan ME et al. (2001). Involvement of chemokine receptors in breast cancer metastasis. Nature 410: 50–56.

    Article  CAS  PubMed  Google Scholar 

  • Muller WJ, Sinn E, Pattengale PK, Wallace R, Leder P . (1988). Single-step induction of mammary adenocarcinoma in transgenic mice bearing the activated c-neu oncogene. Cell 54: 105–115.

    Article  CAS  PubMed  Google Scholar 

  • Muthuswamy SK, Gilman M, Brugge JS . (1999). Controlled dimerization of ErbB receptors provides evidence for differential signaling by homo- and heterodimers. Mol Cell Biol 19: 6845–6857.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Muthuswamy SK, Li D, Lelievre S, Bissell MJ, Brugge JS . (2001). ErbB2, but not ErbB1, reinitiates proliferation and induces luminal repopulation in epithelial acini. Nat Cell Biol 3: 785–792.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Muthuswamy SK, Muller WJ . (1995a). Activation of Src family kinases in Neu-induced mammary tumors correlates with their association with distinct sets of tyrosine phosphorylated proteins in vivo. Oncogene 11: 1801–1810.

    CAS  PubMed  Google Scholar 

  • Muthuswamy SK, Muller WJ . (1995b). Direct and specific interaction of c-Src with Neu is involved in signaling by the epidermal growth factor receptor. Oncogene 11: 271–279.

    CAS  PubMed  Google Scholar 

  • Muthuswamy SK, Siegel PM, Dankort DL, Webster MA, Muller WJ . (1994). Mammary tumors expressing the neu proto-oncogene possess elevated c-Src tyrosine kinase activity. Mol Cell Biol 14: 735–743.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Neve RM, Ylstra B, Chang CH, Albertson DG, Benz CC . (2002). ErbB2 activation of ESX gene expression. Oncogene 21: 3934–3938.

    Article  CAS  PubMed  Google Scholar 

  • Newman L, Xia W, Yang HY, Sahin A, Bondy M, Lukmanji F et al. (2001). Correlation of p27 protein expression with HER-2/neu expression in breast cancer. Mol Carcinog 30: 169–175.

    Article  CAS  PubMed  Google Scholar 

  • Olayioye MA, Neve RM, Lane HA, Hynes NE . (2000). The ErbB signaling network: receptor heterodimerization in development and cancer. (Review) (126 refs). EMBO J 19: 3159–3167.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ottenhoff-Kalff AE, Rijksen G, van Beurden EA, Hennipman A, Michels AA, Staal GE . (1992). Characterization of protein tyrosine kinases from human breast cancer: involvement of the c-src oncogene product. Cancer Res 52: 4773–4778.

    CAS  PubMed  Google Scholar 

  • Paez J, Sellers WR . (2003). PI3K/PTEN/AKT pathway. A critical mediator of oncogenic signaling. Cancer Treat Res 115: 145–167.

    Article  CAS  PubMed  Google Scholar 

  • Park K, Han S, Kim HJ, Kim J, Shin E . (2006). HER2 status in pure ductal carcinoma in situ and in the intraductal and invasive components of invasive ductal carcinoma determined by fluorescence in situ hybridization and immunohistochemistry. Histopathology 48: 702–707.

    Article  CAS  PubMed  Google Scholar 

  • Pellikainen JM, Ropponen KM, Kataja VV, Kellokoski JK, Eskelinen MJ, Kosma VM . (2004). Expression of matrix metalloproteinase (MMP)-2 and MMP-9 in breast cancer with a special reference to activator protein-2, HER2, and prognosis. Clin Cancer Res 10: 7621–7628.

    Article  CAS  PubMed  Google Scholar 

  • Perou CM, Sorlie T, Eisen MB, van de RM, Jeffrey SS, Rees CA et al. (2000). Molecular portraits of human breast tumours. Nature 406: 747–752.

    Article  CAS  PubMed  Google Scholar 

  • Plowman GD, Culouscou JM, Whitney GS, Green JM, Carlton GW, Foy L et al. (1993). Ligand-specific activation of HER4/p180erbB4, a fourth member of the epidermal growth factor receptor family. Proc Natl Acad Sci USA 90: 1746–1750.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Prenzel N, Fischer OM, Streit S, Hart S, Ullrich A . (2001). The epidermal growth factor receptor family as a central element for cellular signal transduction and diversification. Endocr Relat Cancer 8: 11–31.

    Article  CAS  PubMed  Google Scholar 

  • Press MF, Cordon-Cardo C, Slamon DJ . (1990). Expression of the HER-2/neu proto-oncogene in normal human adult and fetal tissues. Oncogene 5: 953–962.

    CAS  PubMed  Google Scholar 

  • Prigent SA, Gullick WJ . (1994). Identification of c-erbB-3 binding sites for phosphatidylinositol 3′-kinase and SHC using an EGF receptor/c-erbB-3 chimera. EMBO J 13: 2831–2841.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ram TG, Ethier SP . (1996). Phosphatidylinositol 3-kinase recruitment by p185erbB-2 and erbB-3 is potently induced by neu differentiation factor/heregulin during mitogenesis and is constitutively elevated in growth factor-independent breast carcinoma cells with c-erbB-2 gene amplification. Cell Growth Differ 7: 551–561.

    CAS  PubMed  Google Scholar 

  • Ramsauer VP, Carraway CA, Salas PJ, Carraway KL . (2003). Muc4/sialomucin complex, the intramembrane ErbB2 ligand, translocates ErbB2 to the apical surface in polarized epithelial cells. J Biol Chem 278: 30142–30147.

    Article  CAS  PubMed  Google Scholar 

  • Real FX, Rettig WJ, Chesa PG, Melamed MR, Old LJ, Mendelsohn J . (1986). Expression of epidermal growth factor receptor in human cultured cells and tissues: relationship to cell lineage and stage of differentiation. Cancer Res 46: 4726–4731.

    CAS  PubMed  Google Scholar 

  • Reddy HK, Mettus RV, Rane SG, Grana X, Litvin J, Reddy EP . (2005). Cyclin-dependent kinase 4 expression is essential for neu-induced breast tumorigenesis. Cancer Res 65: 10174–10178.

    Article  CAS  PubMed  Google Scholar 

  • Reissig D, Clement J, Sanger J, Berndt A, Kosmehl H, Bohmer FD . (2001). Elevated activity and expression of Src-family kinases in human breast carcinoma tissue versus matched non-tumor tissue. J Cancer Res Clin Oncol 127: 226–230.

    Article  CAS  PubMed  Google Scholar 

  • Riethmacher D, Sonnenberg-Riethmacher E, Brinkmann V, Yamaai T, Lewin GR, Birchmeier C . (1997). Severe neuropathies in mice with targeted mutations in the ErbB3 receptor. Nature 389: 725–730.

    Article  CAS  PubMed  Google Scholar 

  • Ritland SR, Rowse GJ, Chang Y, Gendler SJ . (1997). Loss of heterozygosity analysis in primary mammary tumors and lung metastases of MMTV-MTAg and MMTV-neu transgenic mice. Cancer Res 57: 3520–3525.

    CAS  PubMed  Google Scholar 

  • Roh H, Pippin J, Drebin JA . (2000). Down-regulation of HER2/neu expression induces apoptosis in human cancer cells that overexpress HER2/neu. Cancer Res 60: 560–565.

    CAS  PubMed  Google Scholar 

  • Ross JS, Fletcher JA, Linette GP, Stec J, Clark E, Ayers M et al. (2003). The Her-2/neu gene and protein in breast cancer 2003: biomarker and target of therapy. Oncologist 8: 307–325.

    Article  CAS  PubMed  Google Scholar 

  • Saitou M, Goto M, Horinouchi M, Tamada S, Nagata K, Hamada T et al. (2005). MUC4 expression is a novel prognostic factor in patients with invasive ductal carcinoma of the pancreas. J Clin Pathol 58: 845–852.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schechter AL, Hung MC, Vaidyanathan L, Weinberg RA, Yang-Feng TL, Francke U et al. (1985). The neu gene: an erbB-homologous gene distinct from and unlinked to the gene encoding the EGF receptor. Science 229: 976–978.

    Article  CAS  PubMed  Google Scholar 

  • Schechter AL, Stern DF, Vaidyanathan L, Decker SJ, Drebin JA, Greene MI et al. (1984). The neu oncogene: an erb-B-related gene encoding a 185,000-Mr tumour antigen. Nature 312: 513–516.

    Article  CAS  PubMed  Google Scholar 

  • Schiffer IB, Gebhard S, Heimerdinger CK, Heling A, Hast J, Wollscheid U et al. (2003). Switching off HER-2/neu in a tetracycline-controlled mouse tumor model leads to apoptosis and tumor-size-dependent remission. Cancer Res 63: 7221–7231.

    CAS  PubMed  Google Scholar 

  • Schulze WX, Deng L, Mann M . (2005). Phosphotyrosine interactome of the ErbB-receptor kinase family. Mol Syst Biol 10: doi: 10.1038/msb4100012.

  • Segatto O, King CR, Pierce JH, Di Fiore PP, Aaronson SA . (1988). Different structural alterations upregulate in vitro tyrosine kinase activity and transforming potency of the erbB-2 gene. Mol Cell Biol 8: 5570–5574.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Seton-Rogers SE, Lu Y, Hines LM, Koundinya M, LaBaer J, Muthuswamy SK et al. (2004). Cooperation of the ErbB2 receptor and transforming growth factor beta in induction of migration and invasion in mammary epithelial cells. Proc Natl Acad Sci USA 101: 1257–1262.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sheffield LG . (1998). C-Src activation by ErbB2 leads to attachment-independent growth of human breast epithelial cells. Biochem Biophys Res Commun 250: 27–31.

    Article  CAS  PubMed  Google Scholar 

  • Shelly M, Mosesson Y, Citri A, Lavi S, Zwang Y, Melamed-Book N et al. (2003). Polar expression of ErbB-2/HER2 in epithelia. Bimodal regulation by Lin-7. Dev Cell 5: 475–486.

    Article  CAS  PubMed  Google Scholar 

  • Shepherd TG, Kockeritz L, Szrajber MR, Muller WJ, Hassell JA . (2001). The pea3 subfamily ets genes are required for HER2/Neu-mediated mammary oncogenesis. Curr Biol 11: 1739–1748.

    Article  CAS  PubMed  Google Scholar 

  • Shibahara H, Tamada S, Higashi M, Goto M, Batra SK, Hollingsworth MA et al. (2004). MUC4 is a novel prognostic factor of intrahepatic cholangiocarcinoma-mass forming type. Hepatology 39: 220–229.

    Article  CAS  PubMed  Google Scholar 

  • Shigematsu H, Takahashi T, Nomura M, Majmudar K, Suzuki M, Lee H et al. (2005). Somatic mutations of the HER2 kinase domain in lung adenocarcinomas. Cancer Res 65: 1642–1646.

    Article  CAS  PubMed  Google Scholar 

  • Shih C, Padhy LC, Murray M, Weinberg RA . (1981). Transforming genes of carcinomas and neuroblastomas introduced into mouse fibroblasts. Nature 290: 261–264.

    Article  CAS  PubMed  Google Scholar 

  • Shin I, Yakes FM, Rojo F, Shin NY, Bakin AV, Baselga J et al. (2002). PKB/Akt mediates cell-cycle progression by phosphorylation of p27(Kip1) at threonine 157 and modulation of its cellular localization. Nat Med 8: 1145–1152.

    Article  CAS  PubMed  Google Scholar 

  • Sibilia M, Steinbach JP, Stingl L, Aguzzi A, Wagner EF . (1998). A strain-independent postnatal neurodegeneration in mice lacking the EGF receptor. EMBO J 17: 719–731.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sibilia M, Wagner EF . (1995). Strain-dependent epithelial defects in mice lacking the EGF receptor [published erratum appears in Science 1995 Aug 18;269(5226):909]. Science 269: 234–238.

    Article  CAS  PubMed  Google Scholar 

  • Siegel PM, Dankort DL, Hardy WR, Muller WJ . (1994). Novel activating mutations in the neu proto-oncogene involved in induction of mammary tumors. Mol Cell Biol 14: 7068–7077.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Siegel PM, Muller WJ . (1996). Mutations affecting conserved cysteine residues within the extracellular domain of Neu promote receptor dimerization and activation. Proc Natl Acad Sci USA 93: 8878–8883.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Siegel PM, Ryan ED, Cardiff RD, Muller WJ . (1999). 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 18: 2149–2164.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sierke SL, Cheng K, Kim HH, Koland JG . (1997). Biochemical characterization of the protein tyrosine kinase homology domain of the ErbB3 (HER3) receptor protein. Biochem J 322: 757–763.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL . (1987). Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235: 177–182.

    Article  CAS  PubMed  Google Scholar 

  • Slamon DJ, Godolphin W, Jones LA, Holt JA, Wong SG, Keith DE et al. (1989). Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 244: 707–712.

    Article  CAS  PubMed  Google Scholar 

  • Sliwkowski MX . (2003). Ready to partner. Nat Struct Biol 10: 158–159.

    Article  CAS  PubMed  Google Scholar 

  • Sliwkowski MX, Schaefer G, Akita RW, Lofgren JA, Fitzpatrick VD, Nuijens A et al. (1994). Coexpression of erbB2 and erbB3 proteins reconstitutes a high affinity receptor for heregulin. J Biol Chem 269: 14661–14665.

    CAS  PubMed  Google Scholar 

  • Soltoff SP, Carraway III KL, Prigent SA, Gullick WG, Cantley LC . (1994). ErbB3 is involved in activation of phosphatidylinositol 3-kinase by epidermal growth factor. Mol Cell Biol 14: 3550–3558.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Spangenberg C, Lausch EU, Trost TM, Prawitt D, May A, Keppler R et al. (2006). ERBB2-mediated transcriptional up-regulation of the alpha5beta1 integrin fibronectin receptor promotes tumor cell survival under adverse conditions. Cancer Res 66: 3715–3725.

    Article  CAS  PubMed  Google Scholar 

  • Spataro VJ, Litman H, Viale G, Maffini F, Masullo M, Golouh R et al. (2003). Decreased immunoreactivity for p27 protein in patients with early-stage breast carcinoma is correlated with HER-2/neu overexpression and with benefit from one course of perioperative chemotherapy in patients with negative lymph node status: results from International Breast Cancer Study Group Trial V. Cancer 97: 1591–1600.

    Article  CAS  PubMed  Google Scholar 

  • Stephens P, Hunter C, Bignell G, Edkins S, Davies H, Teague J et al. (2004). Lung cancer: intragenic ERBB2 kinase mutations in tumours. Nature 431: 525–526.

    Article  CAS  PubMed  Google Scholar 

  • Subbaramaiah K, Norton L, Gerald W, Dannenberg AJ . (2002). Cyclooxygenase-2 is overexpressed in HER-2/neu-positive breast cancer: evidence for involvement of AP-1 and PEA3. J Biol Chem 277: 18649–18657.

    Article  CAS  PubMed  Google Scholar 

  • Swede H, Moysich KB, Freudenheim JL, Quirk JT, Muti PC, Hurd TC et al. (2001). Breast cancer risk factors and HER2 over-expression in tumors. Cancer Detect Prev 25: 511–519.

    CAS  PubMed  Google Scholar 

  • Tamada S, Shibahara H, Higashi M, Goto M, Batra SK, Imai K et al. (2006). MUC4 is a novel prognostic factor of extrahepatic bile duct carcinoma. Clin Cancer Res 12: 4257–4264.

    Article  CAS  PubMed  Google Scholar 

  • Tan M, Li P, Klos KS, Lu J, Lan KH, Nagata Y et al. (2005a). ErbB2 promotes Src synthesis and stability: novel mechanisms of Src activation that confer breast cancer metastasis. Cancer Res 65: 1858–1867.

    Article  CAS  PubMed  Google Scholar 

  • Tan M, Li P, Klos KS, Lu J, Lan KH, Nagata Y et al. (2005b). ErbB2 promotes Src synthesis and stability: novel mechanisms of Src activation that confer breast cancer metastasis. Cancer Res 65: 1858–1867.

    Article  CAS  PubMed  Google Scholar 

  • Tanner MM, Tirkkonen M, Kallioniemi A, Isola J, Kuukasjarvi T, Collins C et al. (1996). Independent amplification and frequent co-amplification of three nonsyntenic regions on the long arm of chromosome 20 in human breast cancer. Cancer Res 56: 3441–3445.

    CAS  PubMed  Google Scholar 

  • Testa JR, Bellacosa A . (2001). AKT plays a central role in tumorigenesis. Proc Natl Acad Sci USA 98: 10983–10985.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Threadgill DW, Dlugosz AA, Hansen LA, Tennenbaum T, Lichti U, Yee D et al. (1995). Targeted disruption of mouse EGF receptor: effect of genetic background on mutant phenotype. Science 269: 230–234.

    Article  CAS  PubMed  Google Scholar 

  • Timms JF, White SL, O’Hare MJ, Waterfield MD . (2002). Effects of ErbB-2 overexpression on mitogenic signalling and cell cycle progression in human breast luminal epithelial cells. Oncogene 21: 6573–6586.

    Article  CAS  PubMed  Google Scholar 

  • tires-Alj M, Neel BG . (2007). Protein-tyrosine phosphatase 1B Is required for HER2/Neu-induced breast cancer. Cancer Res 67: 2420–2424.

    Article  Google Scholar 

  • Tokunaga E, Kimura Y, Oki E, Ueda N, Futatsugi M, Mashino K et al. (2006). Akt is frequently activated in HER2/neu-positive breast cancers and associated with poor prognosis among hormone-treated patients. Int J Cancer 118: 284–289.

    Article  CAS  PubMed  Google Scholar 

  • Tsuda H, Akiyama F, Terasaki H, Hasegawa T, Kurosumi M, Shimadzu M et al. (2001). Detection of HER-2/neu (c-erb B-2) DNA amplification in primary breast carcinoma. Interobserver reproducibility and correlation with immunohistochemical HER-2 overexpression. Cancer 92: 2965–2974.

    Article  CAS  PubMed  Google Scholar 

  • Tsutsumida H, Goto M, Kitajima S, Kubota I, Hirotsu Y, Wakimoto J et al. (2006). MUC4 expression correlates with poor prognosis in small-sized lung adenocarcinoma. Lung Cancer 55: 195–203.

    Article  PubMed  Google Scholar 

  • Tzahar E, Waterman H, Chen X, Levkowitz G, Karunagaran D, Lavi S et al. (1996). A hierarchical network of interreceptor interactions determines signal transduction by Neu differentiation factor/neuregulin and epidermal growth factor. Mol Cell Biol 16: 5276–5287.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vadlamudi R, Mandal M, Adam L, Steinbach G, Mendelsohn J, Kumar R . (1999). Regulation of cyclooxygenase-2 pathway by HER2 receptor. Oncogene 18: 305–314.

    Article  CAS  PubMed  Google Scholar 

  • Vadlamudi RK, Sahin AA, Adam L, Wang RA, Kumar R . (2003). Heregulin and HER2 signaling selectively activates c-Src phosphorylation at tyrosine 215. FEBS Lett 543: 76–80.

    Article  CAS  PubMed  Google Scholar 

  • Vartanian T, Goodearl A, Lefebvre S, Park SK, Fischbach G . (2000). Neuregulin induces the rapid association of focal adhesion kinase with the erbB2-erbB3 receptor complex in schwann cells. Biochem Biophys Res Commun 271: 414–417.

    Article  CAS  PubMed  Google Scholar 

  • Venter DJ, Tuzi NL, Kumar S, Gullick WJ . (1987). Overexpression of the c-erbB-2 oncoprotein in human breast carcinomas: immunohistological assessment correlates with gene amplification. Lancet 2: 69–72.

    Article  CAS  PubMed  Google Scholar 

  • Viglietto G, Motti ML, Bruni P, Melillo RM, D’Alessio A, Califano D et al. (2002). Cytoplasmic relocalization and inhibition of the cyclin-dependent kinase inhibitor p27(Kip1) by PKB/Akt-mediated phosphorylation in breast cancer. Nat Med 8: 1136–1144.

    Article  CAS  PubMed  Google Scholar 

  • Vijapurkar U, Kim MS, Koland JG . (2003). Roles of mitogen-activated protein kinase and phosphoinositide 3′-kinase in ErbB2/ErbB3 coreceptor-mediated heregulin signaling. Exp Cell Res 284: 291–302.

    Article  CAS  PubMed  Google Scholar 

  • Vivanco I, Sawyers CL . (2002). The phosphatidylinositol 3-kinase AKT pathway in human cancer. [Review] [156 refs]. Nat Rev Cancer 2: 489–501.

    Article  CAS  PubMed  Google Scholar 

  • Wallasch C, Weiss FU, Niederfellner G, Jallal B, Issing W, Ullrich A . (1995b). Heregulin-dependent regulation of HER2/neu oncogenic signaling by heterodimerization with HER3. EMBO J 14: 4267–4275.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wallasch C, Weiss FU, Niederfellner G, Jallal B, Issing W, Ullrich A . (1995a). Heregulin-dependent regulation of HER2/neu oncogenic signaling by heterodimerization with HER3. EMBO J 14: 4267–4275.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang B, Kennan WS, Yasukawa-Barnes J, Lindstrom MJ, Gould MN . (1991). Frequent induction of mammary carcinomas following neu oncogene transfer into in situ mammary epithelial cells of susceptible and resistant rat strains. Cancer Res 51: 5649–5654.

    CAS  PubMed  Google Scholar 

  • Wang SC, Lien HC, Xia W, Chen IF, Lo HW, Wang Z et al. (2004). Binding at and transactivation of the COX-2 promoter by nuclear tyrosine kinase receptor ErbB-2. Cancer Cell 6: 251–261.

    Article  CAS  PubMed  Google Scholar 

  • Wang SE, Narasanna A, Perez-Torres M, Xiang B, Wu FY, Yang S et al. (2006). HER2 kinase domain mutation results in constitutive phosphorylation and activation of HER2 and EGFR and resistance to EGFR tyrosine kinase inhibitors. Cancer Cell 10: 25–38.

    Article  CAS  PubMed  Google Scholar 

  • Wang Z, Zhang L, Yeung TK, Chen X . (1999). Endocytosis deficiency of epidermal growth factor (EGF) receptor-ErbB2 heterodimers in response to EGF stimulation. Mol Biol Cell 10: 1621–1636.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Waterman H, Sabanai I, Geiger B, Yarden Y . (1998). Alternative intracellular routing of ErbB receptors may determine signaling potency. J Biol Chem 273: 13819–13827.

    Article  CAS  PubMed  Google Scholar 

  • Weigelt B, Hu Z, He X, Livasy C, Carey LA, Ewend MG et al. (2005). Molecular portraits and 70-gene prognosis signature are preserved throughout the metastatic process of breast cancer. Cancer Res 65: 9155–9158.

    Article  CAS  PubMed  Google Scholar 

  • Weiner DB, Kokai Y, Wada T, Cohen JA, Williams WV, Greene MI . (1989a). Linkage of tyrosine kinase activity with transforming ability of the p185neu oncoprotein. Oncogene 4: 1175–1183.

    CAS  PubMed  Google Scholar 

  • Weiner DB, Liu J, Cohen JA, Williams WV, Greene MI . (1989b). A point mutation in the neu oncogene mimics ligand induction of receptor aggregation. Nature 339: 230–231.

    Article  CAS  PubMed  Google Scholar 

  • Weinstein EJ, Kitsberg DI, Leder P . (2000). A mouse model for breast cancer induced by amplification and overexpression of the neu promoter and transgene. Mol Med 6: 4–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Weinstein IB . (2002). CANCER: Enhanced: Addiction to Oncogenes – the Achilles Heal of Cancer. Science 297: 63–64.

    Article  CAS  PubMed  Google Scholar 

  • Wilson GR, Cramer A, Welman A, Knox F, Swindell R, Kawakatsu H et al. (2006). Activated c-SRC in ductal carcinoma in situ correlates with high tumour grade, high proliferation and HER2 positivity. Br J Cancer 95: 1410–1414.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Woods Ignatoski KM, Grewal NK, Markwart S, Livant DL, Ethier SP . (2003). p38MAPK induces cell surface alpha4 integrin downregulation to facilitate erbB-2-mediated invasion. Neoplasia 5: 128–134.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xie D, Shu XO, Deng Z, Wen WQ, Creek KE, Dai Q et al. (2000). Population-based, case–control study of HER2 genetic polymorphism and breast cancer risk. J Natl Cancer Inst 92: 412–417.

    Article  CAS  PubMed  Google Scholar 

  • Xie W, Chow LT, Paterson AJ, Chin E, Kudlow JE . (1999). Conditional expression of the ErbB2 oncogene elicits reversible hyperplasia in stratified epithelia and up-regulation of TGFalpha expression in transgenic mice. Oncogene 18: 3593–3607.

    Article  CAS  PubMed  Google Scholar 

  • Xie W, Paterson AJ, Chin E, Nabell LM, Kudlow JE . (1997). Targeted expression of a dominant negative epidermal growth factor receptor in the mammary gland of transgenic mice inhibits pubertal mammary duct development. Mol Endocrinol 11: 1766–1781.

    Article  CAS  PubMed  Google Scholar 

  • Xie W, Wu X, Chow LT, Chin E, Paterson AJ, Kudlow JE . (1998). Targeted expression of activated erbB-2 to the epidermis of transgenic mice elicits striking developmental abnormalities in the epidermis and hair follicles. Cell Growth Differ 9: 313–325.

    CAS  PubMed  Google Scholar 

  • Xie Y, Hung MC . (1994). Nuclear localization of p185neu tyrosine kinase and its association with transcriptional transactivation. Biochem Biophys Res Commun 203: 1589–1598.

    Article  CAS  PubMed  Google Scholar 

  • Xu W, Yuan X, Beebe K, Xiang Z, Neckers L . (2007). Loss of Hsp90 association up-regulates Src-dependent ErbB2 activity. Mol Cell Biol 27: 220–228.

    Article  CAS  PubMed  Google Scholar 

  • Yang C, Ionescu-Tiba V, Burns K, Gadd M, Zukerberg L, Louis DN et al. (2004). The role of the cyclin D1-dependent kinases in ErbB2-mediated breast cancer. Am J Pathol 164: 1031–1038.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang HY, Shao R, Hung MC, Lee MH . (2001). p27 Kip1 inhibits HER2/neu-mediated cell growth and tumorigenesis. Oncogene 20: 3695–3702.

    Article  CAS  PubMed  Google Scholar 

  • Yang HY, Zhou BP, Hung MC, Lee MH . (2000). Oncogenic signals of HER-2/neu in regulating the stability of the cyclin-dependent kinase inhibitor p27. J Biol Chem 275: 24735–24739.

    Article  CAS  PubMed  Google Scholar 

  • Yano T, Doi T, Ohtsu A, Boku N, Hashizume K, Nakanishi M et al. (2006). Comparison of HER2 gene amplification assessed by fluorescence in situ hybridization and HER2 protein expression assessed by immunohistochemistry in gastric cancer. Oncol Rep 15: 65–71.

    PubMed  Google Scholar 

  • Yarden Y, Sliwkowski MX . (2001). Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2: 127–137.

    Article  CAS  PubMed  Google Scholar 

  • Yu Q, Geng Y, Sicinski P . (2001). Specific protection against breast cancers by cyclin D1 ablation. Nature 411: 1017–1021.

    Article  CAS  PubMed  Google Scholar 

  • Zhan L, Xiang B, Muthuswamy SK . (2006). Controlled activation of ErbB1/ErbB2 heterodimers promote invasion of three-dimensional organized epithelia in an ErbB1-dependent manner: implications for progression of ErbB2-overexpressing tumors. Cancer Res 66: 5201–5208.

    Article  CAS  PubMed  Google Scholar 

  • Zhou X, Tan M, Stone H V, Klos KS, Lan KH, Yang Y et al. (2004). Activation of the Akt/mammalian target of rapamycin/4E-BP1 pathway by ErbB2 overexpression predicts tumor progression in breast cancers. Clin Cancer Res 10: 6779–6788.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to M M Moasser.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Moasser, M. The oncogene HER2: its signaling and transforming functions and its role in human cancer pathogenesis. Oncogene 26, 6469–6487 (2007). https://doi.org/10.1038/sj.onc.1210477

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1210477

Keywords

  • HER2
  • HER-2
  • ErbB2
  • ErbB-2
  • Neu
  • HER2/Neu

Further reading

Search

Quick links