Abstract
ERBB3, a member of the epidermal growth factor receptor (EGFR) family, is unique in that its tyrosine kinase domain is functionally defective. It is activated by neuregulins, by other ERBB and nonERBB receptors as well as by other kinases, and by novel mechanisms. Downstream it interacts prominently with the phosphoinositol 3-kinase/AKT survival/mitogenic pathway, but also with GRB, SHC, SRC, ABL, rasGAP, SYK and the transcription regulator EBP1. There are likely important but poorly understood roles for nuclear localization and for secreted isoforms. Studies of ERBB3 expression in primary cancers and of its mechanistic contributions in cultured cells have implicated it, with varying degrees of certainty, with causation or sustenance of cancers of the breast, ovary, prostate, certain brain cells, retina, melanocytes, colon, pancreas, stomach, oral cavity and lung. Recent results link high ERBB3 activity with escape from therapy targeting other ERBBs in lung and breast cancers. Thus a wide and centrally important role for ERBB3 in cancer is becoming increasingly apparent. Several approaches for targeting ERBB3 in cancers have been tested or proposed. Small inhibitory RNA (siRNA) to ERBB3 or AKT is showing promise as a therapeutic approach to treatment of lung adenocarcinoma.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Leahy DJ . Structure and function of the epidermal growth factor (EGF/ErbB) family of receptors. Adv Prot Chem 2004; 68: 1–27.
Klapper LN, Kirschbaum MH, Sela M, Yarden Y . Biochemical and clinical implications of the ErbB/HER signaling network of growth factor receptors. Adv Cancer Res 2000; 77: 25–79.
Yarden Y, Sliwkowski MX . Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2001; 2: 127–137.
Jorissen RN, Walker F, Pouliot N, Garrett TPJ, Ward CW, Burgess AW . Epidermal growth factor receptor: mechanisms of activation and signalling. Exp Cell Res 2003; 284: 31–53.
Citri A, Skaria KB, Yarden Y . The deaf and the dumb: the biology of ErbB-2 and ErbB-3. Exp Cell Res 2003; 284: 54–65.
Citri A, Yarden Y . EGF-ERBB signalling: towards the systems level. Nat Rev Mol Cell Biol 2006; 7: 505–516.
Warren CM, Landgraf R . Signaling through ERBB receptors: multiple layers of diversity and control. Cell Signal 2006; 18: 923–933.
Linggi B, Carpenter G . ErbB receptors: new insights on mechanisms and biology. Trends Cell Biol 2006; 16: 649–656.
Mendelsohn J, Baselga J . Epidermal growth factor receptor targeting in cancer. Semin Oncol 2006; 33: 369–385.
Yeon CH, Pegram MD . Anti-erbB-2-antibody trastuzumab in the treatment of HER2-amplified breast cancer. Invest New Drugs 2005; 23: 391–409.
Ziada A, Barqawi A, Glode LM, Varella-Garcia M, Crighton F, Majeski S et al. The use of trastuzumab in the treatment of hormone refractory prostate cancer: phase II trial. Prostate 2004; 60: 332–337.
Safran H, Iannitti D, Ramanathan R, Schwartz JD, Steinhoff M, Nauman C et al. Herceptin and gemcitabine for metastatic pancreatic cancers that overexpress HER-2/neu. Cancer Invest 2004; 22: 706–712.
Ramanthan RK, Hwang JJ, Zamboni WC, Sinicrope FA, Safran H, Wong MK et al. Low overexpression of HER-2/neu in advanced colorectal cancer limits the usefulness of trastuzumab (Herceptin) and irinotecan as therapy. A phase II trial. Cancer Invest 2004; 22: 858–865.
Clamon G, Herndon J, Kern J, Govindan R, Garst J, Watson D et al. Lack of trastuzumab activity in nonsmall cell lung carcinoma with overexpression of erb-B2: 39810: a phase II trial of Cancer and Leukemia Group B. Cancer 2005; 103: 1670–1675.
Gullick WJ . The c-erbB3/HER3 receptor in human cancer. Cancer Surv 1996; 27: 339–349.
Hsieh AC, Moasser MM . Targeting HER proteins in cancer therapy and the role of the non-target HER3. Br J Cancer 2007; 97: 453–457.
Kraus MH, Issing W, Miki T, Popescu NC, Aaronson SA . 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 1989; 86: 9193–9197.
Plowman GD, Whitney GS, Neubauer MG, Green JM, McDonald VL, Todaro GJ et al. Molecular cloning and expression of an additional epidermal growth factor receptor-related gene. Proc Natl Acad Sci USA 1990; 87: 4905–4909.
Zimonjic DB, Rezanka L, DiPaolo JA, Popescu NC . Refined localization of the erbB-3 proto-oncogene by direct visualization of FISH signals on LUT-inverted and contrast-enhanced digital images of DAPI-banded chromosomes. Cancer Genet Cytogenet 1995; 80: 100–102.
Stein RA, Staros JV . Insights into the evolution of the ErbB receptor family and their ligands from sequence analysis. BMC Evol Biol 2006; 6: 79.
Plowman GD, Culouscou JM, Whitney GS, Green JM, Carlton GW, Foy L et al. Ligand-specific activation of HER4/p180erbB4, a fourth member of the epidermal growth factor receptor family. Proc Natl Acad Sci USA 1993; 90: 1746–1750.
Katoh M, Yazaki Y, Sugimura T, Terada M . c-erbB3 gene encodes secreted as well as transmembrane receptor tyrosine kinase. Biochem Biophys Res Commun 1993; 192: 1189–1197.
Lee H, Maihle NJ . Isolation and characterization of four alternate c-erbB3 transcripts expressed in ovarian carcinoma-derived cell lines and normal human tissues. Oncogene 1998; 16: 3243–3252.
Srinivasan R, Leverton KE, Sheldon H, Hurst HC, Sarraf C, Gullick WJ . Intracellular expression of the truncated extracellular domain of c-erbB-3/HER3. Cell Signal 2001; 13: 321–330.
Lee H, Akita RW, Sliwkowski MX, Maihle NJ . A naturally occurring secreted human ErbB3 receptor isoform inhibits heregulin-stimulated activation of ErbB2, ErbB3 and ErbB4. Cancer Res 2001; 61: 4467–4473.
Vakar-Lopez F, Cheng CJ, Kim J, Shi GG, Troncoso P, Tu SM et al. Upregulation of MDA-BF-1, a secreted isoform of ErbB3, in metastatic prostate cancer cells and activated osteoblasts in bone marrow. J Pathol 2004; 203: 688–695.
Wahab-Wahlgren A, Martinelle N, Holst M, Jahnukainen K, Parvinen M, Soder O . EGF stimulates rat spermatogonial DNA synthesis in seminiferous tubule segments in vitro. Mol Cell Endocrinol 2003; 201: 39–46.
Dadoune JP, Pawlak A, Alfonsi MF, Siffroi JP . Identification of transcripts by macroarrays, RT–PCR and in situ hybridization in human ejaculate spermatozoa. Mol Human Reprod 2005; 11: 133–140.
Yoshida Y, Miyamura M, Hamano S, Yoshida M . Expression of growth factor ligands and their receptor mRNAs in bovine ova during in vitro maturation and after fertilization in vitro. J Vet Med Sci 1998; 60: 549–554.
Lim H, Das SK, Dey SK . erbB genes in the mouse uterus: cell-specific signaling by epidermal growth factor (EGF) family of growth factors during implantation. Dev Biol 1998; 204: 97–110.
Klonisch T, Wolf P, Hombach-Klonisch S, Vogt S, Kuechenhoff A, Tetens F et al. Epidermal growth factor-like ligands and erbB genes in the peri-implantation rabbit uterus and blastocyst. Biol Reprod 2001; 64: 1835–1844.
Fried K, Risling M, Tidcombe H, Gassmann M, Lillesaar C . Expression of ErbB3, ErbB4 and neuregulin-1 mRNA during tooth development. Dev Dyn 2002; 224: 356–360.
Kornblum HI, Yanni DS, Easterday MC, Seroogy KB . Expression of the EGF receptor family members ErbB2, ErbB3, and ErbB4 in germinal zones of the developing brain and in neurosphere cultures containing CNS stem cells. Dev Neurosci 2000; 22: 16–24.
Fox IJ, Kornblum HI . Developmental profile of ErbB receptors in murine central nervous system: implications for functional interactions. J Neurosci Res 2005; 79: 584–597.
Skinner A, Hurst HC . Transcriptional regulation of the c-erbB-3 gene in human breast carcinoma cell lines. Oncogene 1993; 8: 3393–3401.
Zhu CH, Huang Y, Oberley LW, Domann FE . A family of AP-2 proteins downregulate manganese superoxide dismutase expression. J Biol Chem 2001; 276: 14407–14413.
Zhu CH, Domann FE . Dominant negative interference of transcription factor AP-2 causes inhibition of ErbB-3 expression and suppresses malignant cell growth. Breast Cancer Res Treat 2002; 71: 47–57.
Bates NP, Hurst HC . An intron 1 enhancer element mediates oestrogen-induced suppression of ERBB2 expression. Oncogene 1997; 15: 473–481.
Revillion F, Pawlowski V, Lhotellier V, Louchez MM, Peyrat JP . mRNA expression of the type I growth factor receptors in the human breast cancer cells MCF-7: regulation by estradiol and tamoxifen. Anticancer Res 2003; 23: 1455–1460.
Folgiero V, Bachelder RE, Bon G, Sacchi A, Falcioni R, Mercurio AM . The α6β4 integrin can regulate ErbB-3 expression: implications for α6β4 signaling and function. Cancer Res 2007; 67: 1645–1652.
Stein RA, Staros JV . Evolutionary analysis of the ErbB receptor and ligand families. J Mol Evol 2000; 50: 397–412.
Yokoe S, Takahashi M, Asahi M, Lee SH, Li W, Osumi D et al. The Asn418-linked N-glycan of ErbB3 plays a crucial role in preventing spontaneous heterodimerization and tumor promotion. Cancer Res 2007; 67: 1935–1942.
Cho H, Leahy DJ . Structure of the extracellular region of HER3 reveals an interdomain tether. Science 2002; 297: 1330–1333.
Burgess AW, Cho HS, Eigenbrot C, Ferguson KM, Garrett TPJ, Leahy DJ et al. An open-and-shut case? Recent insights into the activation of EGF/ErbB receptors. Mol Cell 2003; 12: 541–552.
Bouyain S, Longo PA, Li S, Ferguson KM, Leahy DJ . The extracellular region of ErbB4 adopts a tethered conformation in the absence of ligand. Proc Natl Acad Sci USA 2005; 102: 15024–15029.
Klein P, Mattoon D, Lemmon MA, Schlessinger J . A structure-based model for ligand binding and dimerization of EGF receptors. Proc Natl Acad Sci USA 2004; 101: 929–934.
Mattoon D, Klein P, Lemmon MA, Lax I, Schlessinger J . The tethered configuration of the EGF receptor extracellular domain exerts only a limited control of receptor function. Proc Natl Acad Sci USA 2004; 101: 923–928.
Dawson JP, Bu Z, Lemmon MA . Ligand-induced structural transitions in ErbB receptor extracellular domains. Structure 2007; 15: 942–954.
Singer E, Landgraf R, Horan T, Slamon D, Eisenberg D . Identification of a heregulin binding site in HER3 extracellular domain. J Biol Chem 2001; 276: 44266–44274.
Kani K, Park E, Landgraf R . The extracellular domains of ErbB3 retain high ligand binding affinity at endosome pH and in the locked conformation. Biochemistry 2005; 44: 15842–15857.
Garrett TPJ, McKern NM, Lou M, Elleman TC, Adams TE, Lovrecz GO et al. The crystal structure of a truncated ErbB2 ectodomain reveals an active conformation, poised to interact with other ErbB receptors. Mol Cell 2003; 11: 495–505.
Kani K, Warren CM, Kaddis CS, Loo JA, Landgraf R . Oligomers of ERBB3 have two distinct interfaces that differ in their sensitivity to disruption by heregulin. J Biol Chem 2005; 280: 8238–8247.
Berger MB, Mendrola JM, Lemmon MA . ErbB3/HER3 does not homodimerize upon neuregulin binding at the cell surface. FEBS Lett 2004; 569: 332–336.
Dawson JP, Berger MB, Lin C, Schlessinger J, Lemmon MA, Ferguson KM . Epidermal growth factor receptor dimerization and activation require ligand-induced conformational changes in the dimer interface. Mol Cell Biol 2005; 25: 7734–7742.
Franklin MC, Carey KD, Vajdos FF, Leahy DJ, de Vos AM, Sliwkowski MX . Insights into ErbB signaling from the structure of the ErbB2-pertuzumab complex. Cancer Cell 2004; 5: 317–328.
Landgraf R, Eisenberg D . Heregulin reverses the oligomerization of HER3. Biochem 2000; 39: 8503–8511.
Mendrola JM, Berger MB, King MC, Lemmon MA . The single transmembrane domains of ErbB receptors self-associate in cell membranes. J Biol Chem 2002; 277: 4704–4712.
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.
Prigent SA, Gullick WJ . Identification of c-erbB-3 binding sites for phosphatidylinositol 3′-kinase and SHC using an EGF receptor/c-erbB3 chimera. EMBO J 1994; 13: 2831–2841.
Yoo JY, Hamburger AW . The use of the yeast two hybrid system to evaluate ErbB-3 interactions with SH2 domain containing proteins. Biochem Biophys Res Commun 1998; 251: 903–906.
Schaefer G, Akita RW, Sliwkowski MX . A discrete three-amino acid segment (LVI) at the C-terminal end of kinase-impaired ErbB3 is required for transactivation of ErbB2. J Biol Chem 1999; 274: 859–866.
Hendriks BS, Cook J, Burke JM, Beusmans JM, Lauffenburger DA, de Graaf D . Computational modelling of ErbB family phosphorylation dynamics in response to transforming growth factor alpha and heregulin indicates spatial compartmentation of phosphatase activity. Syst Biol 2006; 153: 22–33.
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.
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.
Levkowitz G, Waterman H, Zamir E, Kam Z, Oved S, Langdon WY et al. c-Cbl/Sli-1 regulates endocytic sorting and ubiquitination of the epidermal growth factor receptor. Genes Dev 1998; 12: 3663–3674.
Waterman H, Alroy I, Strano S, Seger R, Yarden Y . The C terminus of the kinase-defective neuregulin receptor ErbB-3 confers mitogenic superiority and dictates endocytic routing. EMBO J 1999; 18: 3348–3358.
Qiu XB, Goldberg AL . Nrdp1/FLRF is a ubiquitin ligase promoting ubiquitination and degradation of the epidermal growth factor receptor family member, ErbB3. Proc Natl Acad Sci USA 2002; 99: 14843–14848.
Diamonti AJ, Guy PM, Ivanof C, Wong K, Sweeney C, Carraway KL . An RBCC protein implicated in maintenance of steady-state neuregulin receptor levels. Proc Natl Acad Sci USA 2002; 99: 2866–2871.
Wu X, Yen L, Irwin L, Sweeney C, Carraway KL . Stabilization of the E3 ubiquitin ligase Nrdp1 by the deubiquitinating enzyme USP8. Mol Cell Biol 2004; 24: 7748–7757.
Yen L, Cao Z, Wu X, Ingalla ERQ, Baron C, Young LJT et al. Loss of Nrdp1 enhances ErbB2/ErbB3-dependent breast tumor cell growth. Cancer Res 2006; 66: 11279–11286.
Laederich MB, Funes-Duran M, Yen L, Ingalla E, Wu X, Carraway KL et al. The leucine-rich repeat protein LRIG1 is a negative regulator of ErbB family receptor tyrosine kinases. J Biol Chem 2004; 279: 47050–47056.
Warren CM, Kani K, Landgraf R . The N-terminal domains of neuregulin 1 confer signal attenuation. J Biol Chem 2006; 281: 27306–27316.
Wells A, Marti U . Signalling shortcuts: cell-surface receptors in the nucleus? Nat Rev Mol Cell Biol 2002; 3: 697–702.
Carpenter G . Nuclear localization and possible functions of receptor tyrosine kinases. Curr Opin Cell Biol 2003; 15: 143–148.
Lo HW, Hung MC . Nuclear EGFR signaling network in cancers: linking EGFR pathway to cell cycle progression, nitric oxide pathway and patient survival. Br J Cancer 2006; 94: 184–188.
Offterdinger M, Schofer C, Weipoltshammer K, Grunt TW . c-erbB3: a nuclear protein in mammary epithelial cells. J Cell Biol 2002; 157: 929–939.
Kawano O, Sasaki H, Endo K, Suzuki E, Haneda H, Yukiue H et al. ErbB3 mRNA expression correlated with specific clinicopathologic features of Japanese lung cancers. J Surg Res 2007; e-pub ahead of print 11 July.
Zscheppang K, Korenbaum E, Bueter W, Ramadurai SM, Nielsen HC, Dammann CEL . ErbB receptor dimerization, localization, and co-localization in mouse lung type II epithelial cells. Pediatr Pulmonol 2006; 41: 1205–1212.
Koumakpayi IH, Diallo JS, Le Page C, Lessard L, Gleave M, Begin LR et al. Expression and nuclear localization of ErbB3 in prostate cancer. Clin Cancer Res 2006; 12: 2730–2737.
Raabe TD, Deadwyler G, Varga JW, Devries GH . Localization of neuregulin isoforms and erbB receptors in myelinating glial cells. Glia 2004; 45: 197–207.
Falls DL . Neuregulins: functions, forms, and signaling strategies. Exp Cell Res 2003; 284: 14–30.
Stove C, Bracke M . Roles for neuregulins in human cancer. Clin Exp Metast 2004; 21: 665–684.
Breuleux M . Role of heregulin in human cancer. Cell Mol Life Sci 2007; 64: 2358–2377.
Jones JT, Akita RW, Sliwkowski MX . Binding specificities and affinities of egf domains for ErbB receptors. FEBS Lett 1999; 447: 227–231.
Lu HS, Chang D, Philo JS, Zhang K, Narhi LO, Liu N et al. Studies on the structure and function of glycosylated and nonglycosylated neu differentiation factors. Similarities and differences of the α and β isoforms. J Biol Chem 1995; 270: 4784–4791.
Weiss FU, Wallasch C, Campiglio M, Issing W, Ullrich A . Distinct characteristics of heregulin signals mediated by HER3 or HER4. J Cell Physiol 1997; 173: 187–195.
Sweeney C, Fambrough D, Huard C, Diamonti AJ, Lander ES, Cantley LC et al. Growth factor-specific signaling pathway stimulation and gene expression mediated by ErbB receptors. J Biol Chem 2001; 276: 22685–22698.
Crovello CS, Lai C, Cantley LC, Carraway KL . Differential signaling by the epidermal growth factor-like growth factors neuregulin-1 and neuregulin-2. J Biol Chem 1998; 273: 26954–26961.
Nakano N, Higashiyama S, Kajihara K, Endo T, Ishiguro H, Yamada K et al. NTAKα and β isoforms stimulate breast tumor cell growth by means of different receptor combinations. J Biochem 2000; 127: 925–930.
Hijazi MM, Young PE, Dougherty MK, Bressette DS, Cao TT, Pierce JH et al. NRG-3 in human breast cancers: activation of multiple erbB family proteins. Int J Oncol 1998; 13: 1061–1067.
Harari D, Tzahar E, Romano J, Shelly M, Pierce JH, Andrews GC et al. Neuregulin-4: a novel growth factor that acts through the ErbB-4 receptor tyrosine kinase. Oncogene 1999; 18: 2681–2689.
Pinkas-Kramarski R, Shelly M, Guarino BC, Wang LM, Lyass L, Alroy I et al. ErbB tyrosine kinases and the two neuregulin families constitute a ligand-receptor network. Mol Cell Biol 1998; 18: 6090–6101.
Ferrer-Soler L, Vazquez-Martin A, Brunet J, Menendez JA, De Llorens R, Colomer R . An update of the mechanisms of resistance to EGFR-tyrosine kinase inhibitors in breast cancer: Gefitinib (Iressa™)-induced changes in the expression and nucleo-cytoplasmic trafficking of HER-ligands (Review). Int J Mol Med 2007; 20: 3–10.
Sweeney C, Carraway KL . Ligand discrimination by ErbB receptors: differential signaling through differential phosphorylation site usage. Oncogene 2000; 19: 5568–5573.
Yang S, Raymond-Stintz MA, Ying W, Zhang J, Lidke DS, Steinberg SL et al. Mapping ErbB receptors on breast cancer cell membranes during signal transduction. J Cell Science 2007; 120: 2763–2773.
Alimandi M, Wang LM, Bottaro D, Lee CC, Kuo A, Frankel M et al. Epidermal growth factor and betacellulin mediate signal transduction through co-expressed ErbB2 and ErbB3 receptors. EMBO J 1997; 16: 5608–5617.
Pinkas-Kramarski R, Lenferink AEG, Bacus SS, Lyass L, van de Poll MLM, Klapper LN et al. The oncogenic ErbB-2/ErbB-3 heterodimer is a surrogate receptor of the epidermal growth factor and betacellulin. Oncogene 1998; 16: 1249–1258.
Beerli RR, Hynes NE . Epidermal growth factor-related peptides activate distinct subsets of ErbB receptors and differ in their biological activities. J Biol Chem 1996; 271: 6071–6076.
Okwueze MI, Cardwell NL, Pollins AC, Nanney LB . Modulation of porcine wound repair with a transfected ErbB3 gene and relevant EGF-like ligands. J Invest Dermatol 2007; 127: 1030–1041.
Pinkas-Kramarski R, Soussan L, Waterman H, Levkowitz G, Alroy I, Klapper L et al. Diversification of Neu differentiation factor and epidermal growth factor signaling by combinatorial receptor interactions. EMBO J 1996; 15: 2452–2467.
Fernandes AM, Hamburger AW, Gerwin BI . Dominance of ErbB-1 heterodimers in lung epithelial cells overexpressing ErbB-2. Both ErbB-1 and ErbB-2 contribute significantly to tumorigenicity. Am J Respir Cell Mol Biol 1999; 21: 701–709.
Garach-Jehoshua O, Ravid A, Liberman UA, Koren R . 1,25-Dihydroxyvitamin D3 increases the growth-promoting activity of autocrine epidermal growth factor receptor ligands in keratinocytes. Endocrinology 1999; 140: 713–721.
Li Z, Szabolcs M, Terwilliger JD, Efstradiadis A . Prostatic intraepithelial neoplasia and adenocarcinoma in mice expressing a probasin-Neu oncogenic transgene. Carcinogenesis 2006; 27: 1054–1067.
Soltoff SP, Carraway KL, Prigent SA, Gullick WG, Cantley LC . ErbB3 is involved in activation of phosphatidylinositol 3-kinase by epidermal growth factor. Mol Cell Biol 1994; 14: 3550–3558.
Kim HH, Sierke SL, Koland JG . Epidermal growth factor-dependent association of phosphatidylinositol 3-kinase with the erbB3 gene product. J Biol Chem 1994; 269: 24747–24755.
Kim HH, Vijapurkar U, Hellyer NJ, Bravo D, Koland JG . Signal transduction by epidermal growth factor and heregulin via the kinase-deficient ErbB3 protein. Biochem J 1998; 334: 189–195.
Sierke SL, Cheng K, Kim HH, Koland JG . Biochemical characterization of the protein tyrosine kinase homology domain of the ErbB3 (HER3) receptor protein. Biochem J 1997; 322: 757–763.
Fan YX, Wong L, Johnson GR . EGFR kinase possesses a broad specificity for ErbB phosphorylation sites, and ligand increases catalytic-centre activity without affecting substrate-binding affinity. Biochem J 2005; 392: 417–423.
Zhang K, Sun J, Liu N, Wen D, Chang D, Thomason A et al. Transformation of NIH 3T3 cells by HER3 or HER4 receptors requires the presence of HER1 or HER2. J Biol Chem 1996; 271: 3884–3890.
Sliwkowski MX, Schaefer G, Akita RW, Lofgren JA, Fitzpatrick VD, Nuijens A et al. Coexpression of erbB2 and erbB3 proteins reconstitutes a high affinity receptor for heregulin. J Biol Chem 1994; 269: 14661–14665.
Yen L, Benlimame N, Nie ZR, Xiao D, Wang T, Al Moustafa AE et al. Differential regulation of tumor angiogenesis by distinct ErbB homo- and heterodimers. Mol Biol Cell 2002; 13: 4029–4044.
Nagy P, Vereb G, Sebestyen Z, Horvath G, Lockett SJ, Damjanovich S et al. Lipid rafts and the local density of ErbB proteins influence the biological role of homo- and heteroassociations of ErbB2. J Cell Sci 2002; 115: 4251–4262.
Zhang X, Gureasko J, Shen K, Cole PA, Kuriyan J . An allosteric mechanism for activation of the kinase domain of epidermal growth factor receptor. Cell 2006; 125: 1137–1149.
Gamett DC, Pearson G, Cerione RA, Friedberg I . Secondary dimerization between members of the epidermal growth factor receptor family. J Biol Chem 1997; 272: 12052–12056.
Maegawa M, Takeuchi K, Funakoshi E, Kawasaki K, Nishio K, Shimizu N et al. Growth stimulation of non-small cell lung cancer cell lines by antibody against epidermal growth factor receptor promoting formation of ErbB2/ErbB3 heterodimers. Mol Cancer Res 2007; 5: 393–401.
Azios NG, Romero FJ, Denton MC, Doherty JK, Clinton GM . Expression of herstatin, an autoinhibitor of HER-2/neu, inhibits transactivation of HER-3 by HER-2 and blocks EGF activation of the EGF receptor. Oncogene 2001; 20: 5199–5209.
Wehrman TS, Raab WJ, Casipit CL, Doyonnas R, Pomerantz JH, Blau HM . A system for quantifying dynamic protein interactions defines a role for Herceptin in modulating ErbB2 interactions. Proc Natl Acad Sci USA 2006; 103: 19063–19068.
Contessa JN, Abell A, Mikkelsen RB, Valerie K, Schmidt-Ullrich RK . Compensatory ErbB3/c-Src signaling enhances carcinoma cell survival to ionizing radiation. Breast Cancer Res Treat 2006; 95: 17–27.
Ishizawar RC, Miyake T, Parsons SJ . c-Src modulates ErbB2 and ErbB3 heterocomplex formation and function. Oncogene 2007; 26: 3503–3510.
Zhang J, Kalyankrishna S, Wislez M, Thilaganathan N, Saigal B, Wei W et al. SRC-family kinases are activated in non-small cell lung cancer and promote the survival of epidermal growth factor receptor-dependent cell lines. Am J Pathol 2007; 170: 366–376.
Engelman JA, Zejnullahu K, Mitsudomi T, Song Y, Hyland C, Park JO et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 2007; 316: 1039–1043.
Arteaga CL . HER3 and mutant EGFR meet MET. Nature Med 2007; 13: 675–677.
Fu AKY, Fu WY, Cheung J, Tsim KWK, Ip FCF, Wang JH et al. Cdk5 is involved in neuregulin-induced AChR expression at the neuromuscular junction. Nature Neurosci 2001; 4: 374–381.
Fu AKY, Ip FCF, Fu WY, Cheung J, Wang JH, Yung WH et al. Aberrant motor axon projection, acetylcholine receptor clustering, and neurotransmission in cyclin-dependent kinase 5 null mice. Proc Natl Acad Sci USA 2005; 102: 15224–15229.
Li BS, Ma W, Jaffe H, Zheng Y, Takahashi S, Zhang L et al. Cyclin-dependent kinase-5 is involved in neuregulin-dependent activation of phosphatidylinositol 3-kinase and Akt activity mediating neuronal survival. J Biol Chem 2003; 278: 35702–35709.
Kamalati T, Jolin HE, Fry MJ, Crompton MR . Expression of the BRK tyrosine kinase in mammary epithelial cells enhances the coupling of EGF signalling to PI 3-kinase and Akt, via erbB3 phosphorylation. Oncogene 2000; 19: 5471–5476.
Sergina NV, Rausch M, Wang D, Blair J, Hann B, Shokat KM et al. Escape from HER-family tyrosine kinase inhibitor therapy by the kinase-inactive HER3. Nature 2007; 445: 437–441.
Beerli RR, Graus-Porta D, Woods-Cook K, Chen X, Yarden Y, Hynes ME . Neu differentiation factor activation of ErbB-3 and ErbB-4 is cell specific and displays a differential requirement for ErbB-2. Mol Cell Biol 1995; 15: 6496–6505.
Walters DK, French JD, Arendt BK, Jelinek DF . Atypical expression of ErbB3 in myeloma cells: cross-talk between ErbB3 and the interferon-α signaling complex. Oncogene 2003; 22: 3598–3607.
Hemi R, Paz K, Wertheim N, Karasik A, Zick Y, Kanety H . Transactivation of ErbB2 and ErbB3 by tumor necrosis factor-alpha and anisomycin leads to impaired insulin signaling through serine threonine phosphorylation of IRS proteins. J Biol Chem 2002; 277: 8961–8969.
Walters DK, Jelinek DF . A role for Janus kinases in crosstalk between ErbB3 and the interferon-alpha signaling complex in myeloma cells. Oncogene 2004; 23: 1197–1205.
Schulze WX, Deng L, Mann M . Phosphotyrosine interactome of the ErbB-receptor kinase family. Mol Syst Biol 2005; 1: 2005.0008.
Jones RB, Gordus A, Krall JA, MacBeath G . A quantitative protein interaction network for the ErbB receptors using protein microarrays. Nature 2006; 439: 168–174.
Carraway KL, Soltoff SP, Diamonti AJ, Cantley LC . Heregulin stimulates mitogenesis and phosphatidylinositol 3-kinase in mouse fibroblasts transfected with erbB2/neu and erbB3. J Biol Chem 1995; 270: 7111–7116.
Fedi P, Pierce JH, di Fiore PP, Kraus MH . Efficient coupling with phosphatidylinositol 3-kinase, but not phospholipase Cγ or GTPase-activating protein, distinguishes ErbB-3 signaling from that of other ErbB/EGFR family members. Mol Cell Biol 1994; 14: 492–500.
Hellyer NJ, Kim MS, Koland JG . Heregulin-dependent activation of phosphoinositide 3-kinase and Akt via the ErbB2/ErbB3 co-receptor. J Biol Chem 2001; 276: 42153–42161.
Suenaga A, Takada N, Hatakeyama M, Ichikawa M, Yu X, Tomii K et al. Novel mechanism of interaction of p85 subunit of phosphatidylinositol 3-kinase and ErbB3 receptor-derived phosphotyrosyl peptides. J Biol Chem 2005; 280: 1321–1326.
Hellyer NJ, Cheng K, Koland JG . ErbB3 (HER3) interaction with the p85 regulatory subunit of phosphoinositide 3-kinase. Biochem J 1998; 333: 757–763.
Sithanandam G, Smith GT, Masuda A, Takahashi T, Anderson LM, Fornwald LW . Cell cycle activation in lung adenocarcinoma cells by the ErbB3/phosphatidylinositol 3-kinase/Akt pathway. Carcinogenesis 2003; 24: 1581–1592.
Sithanandam G, Smith GT, Fields JR, Fornwald LW, Anderson LM . Alternate paths from epidermal growth factor receptor to Akt in malignant versus nontransformed lung epithelial cells: ErbB3 versus Gab1. Am J Respir Cell Mol Biol 2005; 33: 490–499.
Venkateswarlu S, Dawson DM, St Clair P, Gupta A, Willson JK, Brattain MG . Autocrine heregulin generates growth factor independence and blocks apoptosis in colon cancer cells. Oncogene 2002; 21: 78–86.
Sithanandam G, Fornwald LW, Fields J, Anderson LM . Inactivation of ErbB3 by siRNA promotes apoptosis and attenuates growth and invasiveness of human lung adenocarcinoma cell line A549. Oncogene 2005; 24: 1847–1859.
Holbro T, Beerli RR, Maurer F, Koziczak M, Barbas CF, Hynes NE . The ErbB2/ErbB3 heterodimer functions as an oncogenic unit: ErbB2 requires ErbB3 to drive breast tumor cell proliferation. Proc Natl Acad Sci USA 2003; 100: 8933–8938.
Pero SC, Daly RJ, Krag DN . Grb-7-based molecular therapeutics in cancer. Expert Rev Mol Med 2003; 5: 1–11.
Fiddes RJ, Campbell DH, Janes PW, Sivertsen SP, Sasaki H, Wallasch C et al. Analysis of Grb7 recruitment by heregulin-activated erbB receptors reveals a novel target selectivity for erbB3. J Biol Chem 1998; 273: 7717–7724.
Zhou MM, Harlan JE, Wade WS, Crosby S, Ravichandran KS, Burakoff SJ et al. Binding affinities of tyrosine-phosphorylated peptides to the COOH-terminal SH2 and NH2-terminal phosphotyrosine binding domains of Shc. J Biol Chem 1995; 270: 31119–31123.
Vijapurkar U, Cheng K, Koland JG . Mutation of a Shc binding site tyrosine residue in ErbB3/HER3 blocks heregulin-dependent activation of mitogen-activated protein kinase. J Biol Chem 1998; 273: 20996–21002.
Vijapurkar U, Kim MS, Koland JG . Roles of mitogen-activated protein kinase and phosphoinositide 3′-kinase in ErbB2/ErbB3 coreceptor-mediated heregulin signaling. Exp Cell Biol 2003; 284: 291–302.
Won S, Si J, Colledge M, Ravichandran KS, Froehner SC, Mei L . Neuregulin-increased expression of acetylcholine receptor epsilon-subunit gene requires ErbB interaction with Shc. J Neurochem 1999; 73: 2358–2368.
Todd DG, Mikkelsen RB, Rorrer WK, Valerie K, Schmidt-Ullrich RK . Ionizing radiation stimulates existing signal transduction pathways involving the activation of epidermal growth factor receptor and ERBB-3, and changes of intracellular calcium in A431 human squamous carcinoma cells. J Recept Signal Transduct Res 1999; 19: 885–908.
Sepp-Lorenzino L, Eberhard I, Ma Z, Cho C, Serve H, Liu F et al. Signal transduction pathways induced by heregulin in MDA-MB-453 breast cancer cells. Oncogene 1996; 12: 1679–1687.
Navara CS . The spleen tyrosine kinase (Syk) in human disease, implications for design of tyrosine kinase inhibitor based therapy. Curr Pharm Des 2004; 10: 1739–1744.
Liu J, Kern JA . Neuregulin-1 activates the JAK-STAT pathway and regulates lung epithelial cell proliferation. Am J Respir Cell Mol Biol 2002; 27: 306–313.
Yoo JY, Wang XW, Rishi AK, Lessor T, Xia XM, Gustafson TA et al. Interaction of the PA2G4 (EBP1) protein with ErbB-3 and regulation of this binding by heregulin. Br J Cancer 2000; 82: 683–690.
Xia X, Lessor TJ, Zhang Y, Woodford N, Hamburger AW . Analysis of the expression pattern of Ebp1, an ErbB-3-binding protein. Biochem Biophys Res Comm 2001; 289: 240–244.
Lessor TJ, Yoo JY, Xia X, Woodford N, Hamburger AW . Ectopic expression of the ErbB-3 binding protein ebp1 inhibits growth and induces differentiation of human breast cancer cell lines. J Cell Physiol 2000; 183: 321–329.
Zhang Y, Fondell JD, Wang Q, Xia X, Cheng A, Lu ML et al. Repression of androgen receptor mediated transcription by the ErbB-3 binding protein, Ebp1. Oncogene 2002; 21: 5609–5618.
Lessor TJ, Hamburger AW . Regulation of the ErbB3 binding protein Ebp1 by protein kinase C. Mol Cell Endocrinol 2001; 175: 185–191.
Xia X, Cheng A, Lessor T, Zhang Y, Hamburger AW . Ebp1, an ErbB-3 binding protein, interacts with Rb and affects Rb transcriptional regulation. J Cell Physiol 2001; 187: 209–217.
Zhang Y, Woodford N, Xia X, Hamburger AW . Repression of E2F1-mediated transcription by the ErbB3 binding protein Ebp1 involves histone deacetylases. Nucleic Acids Res 2003; 31: 2168–2177.
Zhang Y, Hamburger AW . Heregulin regulates the ability of ErbB3-binding protein Ebp1 to bind E2F promoter elements and repress E2F-mediated transcription. J Biol Chem 2004; 279: 26126–26133.
Zhang Y, Akinmade D, Hamburger AW . The ErbB3 binding protein Ebp1 interacts with Sin3A to repress E2F1 and AR-mediated transcription. Nucl Acids Res 2005; 33: 6024–6033.
Zhang Y, Hamburger AW . Specificity and heregulin regulation of Ebp1 (ErbB3 binding protein 1) mediated repression of androgen receptor signaling. Br J Cancer 2005; 92: 140–146.
Zhang Y, Wang XW, Jelovac D, Nakanishi T, Yu MH, Akinmade D et al. The ErbB-3 binding protein Ebp1 suppresses androgen receptor-mediated gene transcription and tumorigenesis of prostate cancer cells. Proc Natl Acad Sci USA 2005; 102: 9890–9895.
Akinmade D, Lee M, Zhang Y, Hamburger AW . Ebp1-mediated inhibition of cell growth requires serine 363 phosphorylation. Int J Oncol 2007; 31: 851–858.
Squatrito M, Mancino M, Donzelli M, Areces LB, Draetta GF . EBP1 is a nucleolar growth-regulating protein that is part of pre-ribosomal ribonucleoprotein complexes. Oncogene 2004; 23: 4454–4465.
Squatrito M, Mancino M, Sala L, Draetta GF . Ebp1 is a dsRNA-binding protein associated with ribosomes that modulates eIF2α phosphorylation. Biochem Biophys Res Comm 2006; 344: 859–868.
Liu Z, Ahn JY, Liu X, Ye K . Ebp1 isoforms distinctively regulate cell survival and differentiation. Proc Natl Acad Sci USA 2006; 103: 10917–10922.
Kowalinski E, Bange G, Bradatsch B, Hurt E, Wild K, Sinning I . The crystal structure of Ebp1 reveals a methionine aminopeptidase fold as binding platform for multiple interactions. FEBS Lett 2007; 581: 4450–4454.
Monie TP, Perrin AJ, Birtley JR, Sweeney TR, Karakasiliotis I, Chaudhry Y et al. Structural insights into the transcriptional and translational roles of Ebp1. EMBO J 2007; 26: 3936–3944.
Jiang X, Borgesi RA, McKnight NC, Kaur R, Carpenter CL, Balk SP . Activation of nonreceptor tyrosine kinase Bmx/Etk mediated by phosphoinositide 3-kinase, epidermal growth factor receptor, and ErbB3 in prostate cancer cells. J Biol Chem 2007; 282: 32689–32698.
Thaminy S, Auerbach D, Arnoldo A, Stagljar I . Identification of novel ErbB3-interacting factors using the split-ubiquitin membrane yeast two-hybrid system. Genome Res 2003; 13: 1744–1753.
Knowle D, Ahmed S, Pulakat L . Identification of an interaction between the angiotensin II receptor sub-type AT2 and the ErbB3 receptor, a member of the epidermal growth factor receptor family. Regul Pept 2000; 87: 73–82.
Yoo JY, Hamburger AW . Interaction of the p23/p198 protein with ErbB-3. Gene 1999; 229: 215–221.
Alimandi M, Romano A, Curia MC, Muraro R, Fedi P, Aaronson SA et al. Cooperative signaling of ErbB3 and ErbB2 in neoplastic transformation and human mammary carcinomas. Oncogene 1995; 10: 1813–1821.
Wallasch C, Weiss FU, Niederfellner G, Jallal B, Issing W, Ullrich A . Heregulin-dependent regulation of HER2/neu oncogenic signaling by heterodimerization with HER3. EMBO J 1995; 17: 4267–4275.
Alaoui-Jamali MA, Song DJ, Benlimame N, Yen L, Deng X, Hernandez-Perez M et al. Regulation of multiple tumor microenvironment markers by overexpression of single or pair combinations of ErbB receptors. Cancer Res 2003; 63: 3764–3774.
Edman CF, Prigent SA, Schipper A, Feramisco JR . Identification of ErbB3-stimulated genes using modified representational difference analysis. Biochem J 1997; 323: 113–118.
Darcy KM, Zangani D, Wohlhueter AL, Huang RY, Vaughan MM, Russell JA et al. Changes in ErbB2 (her-2/neu), ErbB3, and ErbB4 during growth, differentiation, and apoptosis of normal rat mammary epithelial cells. J Histochem Cytochem 2000; 48: 63–80.
Stern DF . ErbBs in mammary development. Exp Cell Res 2003; 284: 89–98.
Ram TG, Hosick HL, Ethier SP . Heregulin-beta is especially potent in activating phosphatidylinositol 3-kinase in nontransformed human mammary epithelial cells. J Cell Physiol 2000; 183: 301–313.
Moasser MM, Basso A, Averbuch SD, Rosen N . The tyrosine kinase inhibitor ZD1839 (‘Iressa’) inhibits HER2-driven signaling and suppresses the growth of HER2-overexpressing tumor cells. Cancer Res 2001; 61: 7184–7188.
Li Q, Ahmed S, Loeb JA . Development of an autocrine neuregulin signaling loop with malignant transformation of human breast epithelial cells. Cancer Res 2004; 64: 7078–7085.
Lemoine NR, Barnes DM, Hollywood DP, Hughes CM, Smith P, Dublin E et al. Expression of the ERBB3 gene product in breast cancer. Br J Cancer 1992; 66: 1116–1121.
Way TD, Kao MD, Lin JK . Apigenin induces apoptosis through proteasomal degradation of HER2/neu in HER2/neu-overexpressing breast cancer cells via the phosphatidylinositol 3-kinase/Akt-dependent pathway. J Biol Chem 2004; 279: 4479–4489.
Bieche I, Onody P, Tozlu S, Driouch K, Vidaud M, Lidereau R . Prognostic value of ERBB family mRNA expression in breast carcinomas. Int J Cancer 2003; 106: 758–765.
Chen X, Yeung TK, Wang Z . Enhanced drug resistance in cells coexpressing ErbB2 with EGF receptor or ErbB3. Biochem Biophys Res Commun 2000; 277: 757–763.
Krane IM, Leder P . NDF/heregulin induces persistence of terminal end buds and adenocarcinomas in the mammary glands of transgenic mice. Oncogene 1996; 12: 1781–1788.
Siegel PM, Ryan ED, Cardiff RD, Muller WJ . Elevated expression of activated forms of Neu/ErbB-2 and ErbB-3 are involved in the induction of mammary tumors in transgenic mice: implications for human breast cancer. EMBO J 1999; 18: 2149–2164.
Kim A, Liu B, Ordonez-Ercan D, Alvarez KM, Jones LD, McKimmey C et al. Functional interaction between mouse erbB3 and wild-type rat c-neu in transgenic mouse mammary tumor cells. Breast Cancer Res 2005; 7: R708–R718.
Czerwenka KF, Manavi M, Hosmann J, Jelincic D, Pischinger KI, Battistutti WB et al. Comparative analysis of two-dimensional protein patterns in malignant and normal human breast tissue. Cancer Detect Prev 2001; 25: 268–279.
Quinn CM, Ostrowski JL, Lane SA, Loney DP, Teasdale J, Benson FA . c-erbB-3 protein expression in human breast cancer: comparison with other tumor variables and survival. Histopathology 1994; 25: 247–252.
Naidu R, Yadav M, Nair S, Kutty MK . Expression of c-erbB3 protein in primary breast carcinomas. Br J Cancer 1998; 78: 1385–1390.
Barnes NL, Khavari S, Boland GP, Cramer A, Knox WF, Bundred NJ . Absence of HER4 expression predicts recurrence of ductal carcinoma in situ of the breast. Clin Cancer Res 2005; 11: 2163–2168.
Witton CJ, Reeves JR, Going JJ, Cooke TG, Bartlett JMS . Expression of the HER1-4 family of receptor tyrosine kinases in breast cancer. J Pathol 2003; 200: 290–297.
Ariazi EA, Clark GM, Mertz JE . Estrogen-related receptor α and estrogen-related receptor γ associate with unfavorable and favorable biomarkers, respectively, in human breast cancer. Cancer Res 2002; 62: 6510–6518.
Pawlowski V, Revillion F, Hebbar M, Hornez L, Peyrat JP . Prognostic value of the type I growth factor receptors in a large series of human primary breast cancers quantified with a real-time reverse transcription-polymerase chain reaction assay. Clin Cancer Res 2000; 6: 4217–4225.
Revillion F, Lhotellier V, Hornez L, Bonneterre J, Peyrat JP . ErbB/HER ligands in human breast cancer, and relationships with their receptors, the bio-pathological features and prognosis. Ann Oncol 2008; 19: 73–80.
Di Cristina M, Minenkova O, Pavoni E, Beghetto E, Spadoni A, Felici F et al. A novel approach for identification of tumor-associated antigens expressed on the surface of tumor cells. Int J Cancer 2007; 120: 1293–1303.
Travis A, Pinder SE, Robertson JF, Bell JA, Wencyk P, Gullick WJ et al. C-erbB-3 in human breast carcinoma: expression and relation to prognosis and established prognostic indicators. Br J Cancer 1996; 74: 229–233.
Robinson AG, Turbin D, Thomson T, Yorida E, Ellard S, Bajdik C et al. Molecular predictive factors in patients receiving trastuzumab-based chemotherapy for metastatic disease. Clin Breast Cancer 2006; 7: 254–261.
Knowlden JM, Gee JMW, Seery LT, Farrow L, Gullick WJ, Ellis IO et al. c-erbB3 and c-erbB4 expression is a feature of the endocrine responsive phenotype in clinical breast cancer. Oncogene 1998; 17: 1949–1957.
Tovey S, Dunne B, Witton CJ, Forsyth A, Cooke TG, Bartlett JM . Can molecular markers predict when to implement treatment with aromatase inhibitors in invasive breast cancer?. Clin Cancer Res 2005; 11: 4835–4842.
Luo J, Miller MW . Ethanol enhances erbB-mediated migration of human breast cancer cells in culture. Breast Cancer Res Treat 2000; 63: 61–69.
Kita YA, Barff J, Luo Y, Wen D, Brankow D, Hu S et al. NDF/heregulin stimulates the phosphorylation of Her3/erbB3. FEBS Lett 1994; 349: 139–143.
Kita Y, Tseng J, Horan T, Wen J, Philo J, Chang D et al. ErbB receptor activation, cell morphology changes, and apoptosis induced by anti-Her2 monoclonal antibodies. Biochem Biophys Res Comm 1996; 226: 59–69.
Chan SDH, Antoniucci DM, Fok KS, Alajoki ML, Harkins RN, Thompson SA et al. Heregulin activation of extracellular acidification in mammary carcinoma cells is associated with expression of HER2 and HER3. J Biol Chem 1995; 270: 22608–22613.
Lewis GD, Lofgren JA, McMurtrey AE, Nuijens A, Fendly BM, Bauer KD et al. Growth regulation of human breast and ovarian tumor cells by heregulin: evidence for the requirement of ErbB2 as a critical component in mediating heregulin responsiveness. Cancer Res 1996; 56: 1457–1465.
Adelsman MA, McCarthy JB, Shimizu Y . Stimulation of β1-integrin function by epidermal growth factor and heregulin-β has distinct requirements for erbB2 but a similar dependence on phosphoinositide 3-OH kinase. Mol Biol Cell 1999; 10: 2861–2878.
Harari D, Yarden Y . Molecular mechanisms underlying ErbB2/HER2 action in breast cancer. Oncogene 2000; 19: 6102–6114.
Neve RM, Sutterluty H, Pullen N, Lane HA, Daly JM, Krek W et al. Effects of oncogenic ErbB2 on G1 cell cycle regulators in breast tumor cells. Oncogene 2000; 19: 1647–1656.
Agus DB, Akita RW, Fox WD, Lewis GD, Higgins B, Pisacane PI et al. Targeting ligand-activated ErbB2 signaling inhibits breast and prostate tumor growth. Cancer Cell 2002; 2: 127–137.
Basso AD, Solit DB, Munster PN, Rosen N . Ansamycin antibiotics inhibit Akt activation and cyclin D expression in breast cancer cells that overexpress HER2. Oncogene 2002; 21: 1159–1166.
Yakes FM, Chinratanalab W, Ritter CA, King W, Seelig S, Arteaga CL . Herceptin-induced inhibition of phosphatidylinositol-3 kinase and Akt is required for antibody-mediated effects on p27, cyclin D1, and antitumor action. Cancer Res 2002; 62: 4132–4141.
Knuefermann C, Lu Y, Liu B, Jin W, Liang K, Wu L et al. HER2/PI-3K/Akt activation leads to multidrug resistance in human breast adenocarcinoma cells. Oncogene 2003; 22: 3205–3212.
Xia W, Liu LH, Ho P, Spector NL . Truncated ErbB2 receptor (p95ErbB2) is regulated by heregulin through heterodimer formation with ErbB3 yet remains sensitive to the dual EGFR/ErbB2 kinase inhibitor GW572016. Oncogene 2004; 23: 646–653.
Egeblad M, Jaattela M . Cell death induced by TNF or serum starvation is independent of ErbB receptor signaling in MCF-7 breast carcinoma cells. Int J Cancer 2000; 86: 617–625.
Watt HL, Kumar U . Colocalization of somatostatin receptors and epidermal growth factor receptors in breast cancer cells. Cancer Cell Int 2006; 6: 5.
Brockhoff G, Heiss P, Schlegel J, Hofstaedter F, Knuechel R . Epidermal growth factor receptor, c-erbB2 and c-erbB3 receptor interaction, and related cell cycle kinetics of SK-BR-3 and BT474 breast carcinoma cells. Cytometry 2001; 44: 338–348.
Ram TG, Ethier SP . 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 Diff 1996; 7: 551–561.
Yang C, Liu Y, Lemmon MA, Kazanietz MG . Essential role for Rac in heregulin β1 mitogenic signaling: a mechanism that involves epidermal growth factor receptor and is independent of ErbB4. Mol Cell Biol 2006; 26: 831–842.
Fiddes RJ, Janes PW, Sanderson GM, Sivertsen SP, Sutherland RL, Daly RJ . Heregulin (HRG)-induced mitogenic signaling and cytotoxic activity of a HRG/PE40 ligand toxin in human breast cancer cells. Cell Growth Differ 1995; 6: 1567–1577.
Fiddes RJ, Janes PW, Sivertsen SP, Sutherland RL, Musgrove EA, Daly RJ . Inhibition of the MAP kinase cascade blocks heregulin-induced cell cycle progression in T-47D human breast cancer cells. Oncogene 1998; 16: 2803–2813.
Aguilar Z, Akita RW, Finn RS, Ramos BL, Pegram MD, Kabbinavar FF et al. Biologic effects of heregulin/neu differentiation factor on normal and malignant human breast and ovarian epithelial cells. Oncogene 1999; 18: 6050–6062.
Hijazi MM, Thompson EW, Tang C, Coopman P, Torri JA, Yang D et al. Heregulin regulates the actin cytoskeleton and promotes invasive properties in breast cancer cell lines. Int J Oncol 2000; 17: 629–641.
Vadlamudi R, Adam L, Tseng B, Costa L, Kumar R . Transcriptional up-regulation of paxillin expression by heregulin in human breast cancer cells. Cancer Res 1999; 59: 2843–2846.
Xue C, Liang F, Mahmood R, Vuolo M, Wyckoff J, Qian H et al. ErbB3-dependent motility and intravasation in breast cancer metastasis. Cancer Res 2006; 66: 1418–1426.
Daly JM, Olayioye MA, Wong AM, Neve R, Lane HA, Maurer FG et al. NDF/heregulin-induced cell cycle changes and apoptosis in breast tumour cells: role of PI3 kinase and p38 MAP kinase pathways. Oncogene 1999; 18: 3440–3451.
Van der Horst EH, Murgia M, Treder M, Ullrich A . Anti-HER-3 MAbs inhibit HER-3-mediated signaling in breast cancer cell lines resistant to anti-HER-2 antibodies. Int J Cancer 2005; 115: 519–527.
Ram TG, Schelling ME, Hosick HL . Blocking HER-2/HER-3 function with a dominant negative form of HER-3 in cells stimulated by heregulin and in breast cancer cells with HER-2 gene amplification. Cell Growth Differ 2000; 11: 173–183.
Hutcheson IR, Knowlden JM, Hiscox SE, Barrow D, Gee JM, Robertson JF et al. Heregulin beta1 drives gefitinib-resistant growth and invasion in tamoxifen-resistant MCF-7 breast cancer cells. Breast Cancer Res 2007; 9: R50.
Le XF, Varela CR, Bast RC . Heregulin-induced apoptosis. Apoptosis 2002; 7: 483–491.
Xu FJ, Stack S, Boyer C, O’Briant K, Whitaker R, Mills GB et al. Heregulin and agonistic anti-p185(c-erbB2) antibodies inhibit proliferation but increase invasiveness of breast cancer cells that overexpress p185(c-erbB2): increased invasiveness may contribute to poor prognosis. Clin Cancer Res 1997; 3: 1629–1634.
Hatakeyama M, Zou E, Matsumura F . Comparison of the characteristic of estrogenic action patterns of β-HCH and heregulin β1 in MCF-7 human breast cancer cells. J Biochem Mol Toxicol 2002; 16: 209–219.
Liu B, Ordonez-Ercan D, Fan Z, Edgerton SM, Yang X, Thor AD . Downregulation of erbB3 abrogates erbB2-mediated tamoxifen resistance in breast cancer cells. Int J Cancer 2007; 120: 1874–1882.
Sergina NV, Moasser MM . The HER family and cancer: emerging molecular mechanisms and therapeutic targets. Trends Mol Med 2007; 13: 527–534.
Tsuda H, Birrer MJ, Ito YM, Ohashi Y, Lin M, Lee C et al. Identification of DNA copy number changes in microdissected serous ovarian cancer tissue using a cDNA microarray platform. Cancer Genet Cytogenet 2004; 155: 97–107.
Simpson BJ, Phillips HA, Lessells AM, Langdon SP, Miller WR . c-erbB growth-factor-receptor proteins in ovarian tumours. Int J Cancer 1995; 64: 202–206.
Simpson BJ, Weatherill J, Miller EP, Lessells AM, Langdon SP, Miller WR . c-erbB-3 protein expression in ovarian tumors. Br J Cancer 1995; 71: 758–762.
Shen K, Lang J, Guo L . Overexpression of C-erbB3 in transitional cell carcinoma of the ovary. Zhongua Fu Chan Ke Za Zhi 1995; 30: 658–661.
Rajkumar T, Stamp GW, Hughes CM, Gullick WJ . c-erbB3 protein expression in ovarian cancer. Clin Mol Pathol 1996; 49: M199–M202.
Leng J, Lang J, Shen K, Guo L . Overexpression of p53, EGFR, c-erbB2 and c-erbB3 in endometrioid carcinoma of the ovary. Chin Med Sci J 1997; 12: 67–70.
Gilmour LMR, Macleod KG, McCaig A, Sewell JM, Gullick WJ, Smyth JF et al. Neuregulin expression, function and signaling in human ovarian cancer cells. Clin Cancer Res 2002; 8: 3933–3942.
Campos S, Hamid O, Seiden MV, Oza A, Plante M, Potkul RK et al. Multicenter, randomized phase II trial of oral CI-1033 for previously treated advanced ovarian cancer. J Clin Oncol 2005; 23: 5597–5604.
Li L, Zhong YP, Zhang W, Zhang JQ, Yao ZQ . Relationship of expression of C-erbB2, C-erbB3, and C-erbB4 with ovarian carcinoma. Ai Zheng 2004; 23: 568–572.
Tanner B, Hasenclever D, Stern K, Schormann W, Bezler M, Hermes M et al. ErbB-3 predicts survival in ovarian cancer. J Clin Oncol 2006; 24: 4317–4323.
Campiglio M, Ali S, Knyazev PG, Ullrich A . Characteristics of EGFR family-mediated HRG signals in human ovarian cancer. J Cell Biochem 1999; 73: 522–532.
Mellinghoff IK, Vivanco I, Kwon A, Tran C, Wongvipat J, Sawyers CL . HER2/neu kinase-dependent modulation of androgen receptor function through effects on DNA binding and stability. Cancer Cell 2004; 6: 517–527.
Xin L, Teitell MA, Lawson DA, Kwon A, Mellinghoff IK, Witte ON . Progression of prostate cancer by synergy of AKT with genotropic and nongenotropic actions of the androgen receptor. Proc Natl Acad Sci USA 2006; 103: 7789–7794.
Wang Y, Kreisberg JI, Ghosh PM . Cross-talk between the androgen receptor and the phosphatidylinositol 3-kinase/Akt pathway in prostate cancer. Curr Cancer Drug Targets 2007; 7: 591–604.
Myers RB, Srivastava S, Oelschlager DK, Grizzle WE . Expression of p160erbB-3 and p185erbB-2 in prostatic intraepithelial neoplasia and prostatic adenocarcinoma. J Natl Cancer Inst 1994; 86: 1140–1145.
Leung HY, Weston J, Gullick WJ, Williams G . A potential autocrine loop between heregulin-alpha and erbB-3 receptor in human prostatic adenocarcinoma. Br J Urol 1997; 79: 212–216.
Lyne JC, Melhem MF, Finley GG, Wen D, Liu N, Deng DH et al. Tissue expression of neu differentiation factor/heregulin and its receptor complex in prostate cancer and its biologic effects on prostate cancer cells in vitro. Cancer J Sci Am 1997; 3: 21–30.
Lozano JJ, Soler M, Bermudo R, Abia D, Fernandez PL, Thomson TM et al. Dual activation of pathways regulated by steroid receptors and peptide growth factors in primary prostate cancer revealed by Factor Analysis of microarray data. BMC Genomics 2005; 6: 109.
Chaib H, Cockrell EK, Rubin MA, Macoska JA . Profiling and verification of gene expression patterns in normal and malignant human prostate tissues by cDNA microarray analysis. Neoplasia 2001; 3: 43–52.
Kniazev IuP, Cheburkin IuV, Spikerman K, Peter S, Jenster G, Bangma KH et al. Gene expression profiles of protein kinases and phosphatases obtained by hybridization with cDNA arrays: molecular portrait of human prostate carcinoma. Mol Biol (Mosk) 2003; 37: 97–111.
Robinson D, He F, Pretlow T, Kung HJ . A tyrosine kinase profile of prostate carcinoma. Proc Natl Acad Sci USA 1996; 93: 5958–5962.
Grasso AW, Wen D, Miller CM, Rhim JS, Pretlow TG, Kung HJ . ErbB kinases and NDF signaling in human prostate cancer cells. Oncogene 1997; 15: 2705–2716.
El Sheikh SS, Domin J, Abel P, Stamp G, Lalani el-N . Phosphorylation of both EGFR and ErbB2 is a reliable predictor of prostate cancer cell proliferation in response to EGF. Neoplasia 2004; 6: 846–853.
Agus DB, Akita RW, Fox WD, Lofgren JA, Higgins B, Maiese K et al. A potential role for activated HER-2 in prostate cancer. Semin Oncol 2000; 6 (Suppl 11): 76–83.
Di Lorenzo G, Tortora G, D’Armiento FP, De Rosa G, Staibano S, Autorino R et al. Expression of epidermal growth factor receptor correlates with disease relapse and progression to androgen-independence in human prostate cancer. Clin Cancer Res 2002; 8: 3438–3444.
Le Page C, Koumakpayi IH, Lessard L, Saad F, Mes-Masson AM . Independent role of phosphoinositol-3-kinase (PI3K) and casein kinase II (CK-2) in EGFR and Her-2-mediated constitutive NF-kappaB activation in prostate cancer cells. Prostate 2005; 65: 306–315.
Gross ME, Jo S, Agus DB . Update on HER-kinase-directed therapy in prostate cancer. Clin Adv Hematol Oncol 2004; 2: 53–57.
Hernes E, Fossa SD, Berner A, Otnes B, Nesland JM . Expression of the epidermal growth factor receptor family in prostate carcinoma before and during androgen-independence. Br J Cancer 2004; 90: 449–454.
Mendoza N, Phillips GL, Silva J, Schwall R, Wickramasinghe D . Inhibition of ligand-mediated HER2 activation in androgen-independent prostate cancer. Cancer Res 2002; 62: 5485–5488.
Gregory CW, Whang YE, McCall W, Fei X, Liu Y, Ponguta LA et al. Heregulin-induced activation of HER2 and HER3 increases androgen receptor transactivation and CWR-R1 human recurrent prostate cancer cell growth. Clin Cancer Res 2005; 11: 1704–1712.
Culig Z, Hobisch A, Cronauer MV, Radmayr C, Hittmair A, Zhang J et al. Regulation of prostatic growth and function by peptide growth factors. Prostate 1996; 28: 392–405.
Limonta P, Dondi D, Marelli MM, Moretta RM, Negri-Cesi P, Motta M . Growth of the androgen-dependent tumor of the prostate: role of androgens and of locally expressed growth modulatory factors. J Steroid Biochem Mol Biol 1995; 53: 401–405.
Lin J, Adam RM, Santiestevan E, Freeman MR . The phosphatidylinositol 3′-kinase pathway is a dominant growth factor-activated cell survival pathway in LNCaP human prostate carcinoma cells. Cancer Res 1999; 59: 2891–2897.
Scher HI, Sarkis A, Reuter V, Cohen D, Netto G, Petrylak D et al. Changing pattern of expression of the epidermal growth factor receptor and transforming growth factor alpha in the progression of prostatic neoplasms. Clin Cancer Res 1995; 1: 545–550.
Le Page C, Koumakpayi IH, Lessard L, Mes-Masson AM, Saad F . EGFR and Her-2 regulate the constitutive activation of NF-kappaB in PC-3 prostate cancer cells. Prostate 2005; 65: 130–140.
Torring N, Jorgensen PE, Sorensen BS, Nexo E . Increased expression of heparin binding EGF (HB-EGF), amphiregulin, TGF alpha and epiregulin in androgen-independent prostate cancer cell lines. Anticancer Res 2000; 20: 91–95.
Qiu Y, Ravi L, Kung HJ . Requirement of ErbB2 for signalling by interleukin-6 in prostate carcinoma cells. Nature 1998; 393: 83–85.
Koumakpayi IH, Diallo JS, Le Page C, Lessard L, Filali-Mouhim A, Begin LR et al. Low nuclear ErbB3 predicts biochemical recurrence in patients with prostate cancer. BJU Int 2007; 100: 303–309.
Chen N, Ye XC, Chu K, Navone NM, Sage EH, Yu-Lee LY et al. A secreted isoform of ErbB3 promotes osteonectin expression in bone and enhances the invasiveness of prostate cancer cells. Cancer Res 2007; 67: 6544–6548.
Cheng CJ, Ye XC, Vakar-Lopez F, Kim J, Tu SM, Chen DT et al. Bone microenvironment and androgen status modulate subcellular localization of ErbB3 in prostate cancer cells. Mol Cancer Res 2007; 5: 675–684.
Poller DN, Spendlove I, Baker C, Church R, Ellis IO, Plowman GD et al. Production and characterization of a polyclonal antibody to the c-erbB-3 protein: examination of c-erbB-3 protein expression in adenocarcinomas. J Pathol 1992; 168: 275–280.
Tsai YS, Tzai TS, Chow NH, Wu CL . Frequency and clinicopathologic correlates of ErbB1, ErbB2, and ErbB3 immunoreactivity in urothelial tumors of upper urinary tract. Urology 2005; 66: 1197–1202.
Rajkumar T, Stamp GW, Pandha HS, Waxman J, Gullick WJ . Expression of the type 1 tyrosine kinase growth factor receptors EGF receptor, c-erbB2 and c-erbB3 in bladder cancer. J Pathol 1996; 179: 381–385.
Memon AA, Chang JW, Oh BR, Yoo YJ . Identification of differentially expressed proteins during human urinary bladder cancer progression. Cancer Detect Prev 2005; 29: 249–255.
Memon AA, Sorensen BS, Meldgaard P, Fokdal L, Thykjaer T, Nexo E . The relation between survival and expression of HER1 and HER2 depends on the expression of HER3 and HER4: a study in bladder cancer patients. Br J Cancer 2006; 94: 1703–1709.
Memon AA, Sorensen BS, Nexo E . The epidermal growth factor family has a dual role in deciding the fate of cancer cells. Scand J Clin Lab Invest 2006; 66: 623–630.
Lindholm T, Cullheim S, Deckner M, Carlstedt T, Risling M . Expression of neuregulin and ErbB3 and ErbB4 after a traumatic lesion in the ventral funiculus of the spinal cord and in the intact primary olfactory system. Exp Brain Res 2002; 142: 81–90.
Ozaki M, Kishigami S, Yano R . Expression of receptors for neuregulins, ErbB2, ErbB3 and ErbB4, in developing mouse cerebellum. Neurosci Res 1998; 30: 351–354.
Britsch S, Li L, Kirchhoff S, Theuring F, Brinkmann V, Birchmeier C et al. The ErbB2 and ErbB3 receptors and their ligand, neuregulin-1, are essential for development of the sympathetic nervous system. Genes Dev 1998; 12: 1825–1836.
Levi AD, Bunge RP, Lofgren JA, Meima L, Hefti F, Nikolics K et al. The influence of heregulins on human Schwann cell proliferation. J Neurosci 1995; 15: 1329–1340.
Grinspan JB, Marchionni MA, Reeves M, Coulaloglou M, Scherer SS . Axonal interactions regulate Schwann cell apoptosis in developing peripheral nerve: neuregulin receptors and the role of neuregulins. J Neurosci 1996; 16: 6107–6118.
Davies AM . Neuronal survival: early dependence on Schwann cells. Curr Biol 1998; 8: R15–R18.
Erickson SL, O’Shea KS, Ghaboosi N, Loverro L, Frantz G, Bauer M et al. ErbB3 is required for normal cerebellar and cardiac development: a comparison with ErbB2- and heregulin-deficient mice. Development 1997; 124: 4999–5011.
Riethmacher D, Sonnenberg-Riethmacher E, Brinkmann V, Yamaai T, Lewin GR, Birchmeier C . Severe neuropathies in mice with targeted mutations in the ErbB3 receptor. Nature 1997; 389: 725–730.
Narkis G, Ofir R, Manor E, Landau D, Elbedour K, Birk OS . Lethal congenital contractural syndrome type 2 (LCCS2) is caused by a mutation in ERBB3 (Her3), a modulator of the phosphatidylinositol-3-kinase/Akt pathway. Am J Hum Genet 2007; 81: 589–595.
Steiner H, Blum M, Kitai ST, Fedi P . Differential expression of ErbB3 and ErbB4 neuregulin receptors in dopamine neurons and forebrain areas of the adult rat. Exp Neurol 1999; 159: 494–503.
Gerecke KM, Wyss JM, Karavanova I, Buonanno A, Carroll SL . ErbB transmembrane tyrosine kinase receptors are differentially expressed throughout the adult rat central nervous system. J Comp Neurol 2001; 433: 86–100.
Geuna S, Nicolino S, Raimondo S, Gambarotta G, Battiston B, Tos P et al. Nerve regeneration along bioengineered scaffolds. Microsurgery 2007; 27: 429–438.
Rosenbaum C, Karyala S, Marchionni MA, Kim HA, Krasnoselsky AL, Happel B et al. Schwann cells express NDF and SMDF/n-ARIA mRNAs, secrete neuregulin, and show constitutive activation of erbB3 receptors: evidence for a neuregulin autocrine loop. Exp Neurol 1997; 148: 604–615.
Carroll SL, Miller ML, Frohnert PW, Kim SS, Corbett JA . Expression of neuregulins and their putative receptors, ErbB2 and ErbB3, is induced during Wallerian degeneration. J Neurosci 1997; 17: 1642–1659.
Addo-Yobo SO, Straessle J, Anwar A, Donson AM, Kleinschmidt-Demasters BK, Foreman NK . Paired overexpression of ErbB3 and Sox10 in pilocytic astrocytoma. J Neuropathol Exp Neurol 2006; 65: 769–775.
Bodey B, Kaiser HE, Siegel SE . Epidermal growth factor receptor (EGFR) expression in childhood brain tumors. In Vivo 2005; 19: 931–941.
Gershon TR, Oppenheimer O, Chin SS, Gerald WL . Temporally regulated neural crest transcription factors distinguish neuroectodermal tumors of varying malignancy and differentiation. Neoplasia 2005; 7: 575–584.
Donson AM, Erwin NS, Kleinschmidt-DeMasters BK, Madden JR, Addo-Yobo SO, Foreman NK . Unique molecular characteristics of radiation-induced glioblastoma. J Neuropathol Exp Neurol 2007; 66: 740–749.
Andersson U, Guo D, Malmer B, Bergenheim AT, Brannstrom T, Hedman H et al. Epidermal growth factor receptor family (EGFR, ErbB2-4) in gliomas and meningiomas. Acta Neuropathol 2004; 108: 135–142.
Ritch PA, Carroll SL, Sontheimer H . Neuregulin-1 enhances motility and migration of human astrocytic glioma cells. J Biol Chem 2003; 278: 20971–20978.
Arjona D, Bello MJ, Alonso ME, Gonzalez-Gomez P, Lomas J, Aminoso C et al. Molecular analysis of the erbB gene family calmodulin-binding and calmodulin-like domains in astrocytic gliomas. Int J Oncol 2004; 25: 1489–1494.
Ritch PS, Carroll SL, Sontheimer H . Neuregulin-1 enhances survival of human astrocytic glioma cells. Glia 2005; 51: 217–228.
Schlegel J, Stumm G, Brandle K, Merdes A, Mechtersheimer G, Hynes NE et al. Amplification and differential expression of members of the erbB-gene family in human glioblastoma. J Neurooncol 1994; 22: 201–207.
Westphal M, Meima L, Szonyi E, Lofgren J, Meissner H, Hamel W et al. Heregulins and the ErbB-2/3/4 receptors in gliomas. J Neurooncol 1997; 35: 335–346.
Chakraborty S, Khare S, Dorairaj SK, Prabhakaran VC, Prakash DR, Kumar A . Identification of genes associated with tumorigenesis of retinoblastoma by microarray analysis. Genomics 2007; 90: 344–353.
Gyorffy B, Lage H . A web-based data warehouse on gene expression in human malignant melanoma. J Invest Dermatol 2007; 127: 394–399.
Schaefer KL, Wai DH, Poremba C, Korsching E, van Valen F, Ozaki T et al. Characterization of the malignant melanoma of soft-parts cell line GG-62 by expression analysis using DNA microarrays. Virchows Arch 2002; 440: 476–484.
Schaefer KL, Brachwitz K, Wai DH, Braun Y, Diallo R, Korsching E et al. Expression profiling of t(12:22) positive clear cell sarcoma of soft tissue cell lines reveals characteristic up-regulation of potential new marker genes including ERBB3. Cancer Res 2004; 64: 3395–3405.
Segal NH, Pavlidis P, Nobel WS, Antonescu CR, Viale A, Wesley UV et al. Classification of clear-cell sarcoma as a subtype of melanoma by genomic profiling. J Clin Oncol 2003; 21: 1775–1781.
Bodey B, Kaiser HE, Goldfarb RH . Immunophenotypically varied cell subpopulations in primary and metastatic human melanomas. Monoclonal antibodies for diagnosis, detection of neoplastic progression and receptor directed immunotherapy. Anticancer Res 1996; 16: 517–531.
Bodey B, Bodey B, Groger AM, Luck JV, Siegel SE, Taylor CR et al. Clinical and prognostic significance of the expression of c-erbB-2 and c-erbB-3 oncoproteins in primary and metastatic malignant melanomas and breast carcinomas. Anticancer Res 1997; 17: 1319–1330.
Korabiowska M, Mirecka J, Brinck U, Hoefer K, Marx D, Schauer A . Differential expression of cerbB3 in naevi and malignant melanomas. Anticancer Res 1996; 16: 471–474.
Stove C, Stove V, Derycke L, Van Marck V, Mareel M, Bracke M . The heregulin/human epidermal growth factor receptor as a new growth factor system in melanoma with multiple ways of deregulation. J Invest Dermatol 2003; 121: 802–812.
Soikkeli J, Lukk M, Nummela P, Virolainen S, Jahkola T, Katainen R et al. Systematic search for the best gene expression markers for melanoma micrometastasis detection. J Pathol 2007; 213: 180–189.
Gordon-Thomson C, Jones J, Mason RS, Moore GP . ErbB receptors mediate both migratory and proliferative activities in human melanocytes and melanoma cells. Melanoma Res 2005; 15: 21–28.
Funes M, Miller JK, Lai C, Carraway KL, Sweeney C . The mucin Muc4 potentiates neuregulin signaling by increasing the cell-surface populations of ErbB2 and ErbB3. J Biol Chem 2006; 281: 19310–19319.
Schaefer KL, Brachwitz K, Braun Y, Diallo R, Wai DH, Zahn S et al. Constitutive activation of neuregulin/ERBB3 signaling pathway in clear cell sarcoma of soft tissue. Neoplasia 2006; 8: 613–622.
Rajkumar T, Gooden CSR, Lemoine NR, Gullick WJ, Goden CS . Expression of the C-erbB-3 protein in gastrointestinal tract tumours determined by monoclonal antibody RTJ1. J Pathol 1993; 170: 271–278.
Noguchi H, Sakamoto C, Wada K, Akamatsu T, Uchida T, Tatsuguchi A et al. Expression of heregulin α, erbB2, and erbB3 and their influences on proliferation of gastric epithelial cells. Gastroenteroloy 1999; 117: 1119–1127.
Carver RS, Sliwkowski MX, Sitaric S, Russell WE . Insulin regulates heregulin binding and ErbB3 expression in rat hepatocytes. J Biol Chem 1996; 271: 13491–13496.
Carver RS, Mathew PM, Russell WE . Hepatic expression of ErbB3 is repressed by insulin in a pathway sensitive to PI-3 kinase inhibitors. Endocrinology 1997; 138: 5195–5201.
Jeong EG, Soung YH, Lee JW, Lee SH, Nam SW, Lee JY et al. ERBB3 kinase domain mutations are rare in lung, breast and colon carcinomas. Int J Cancer 2006; 119: 2986–2987.
Ciardiello F, Kim N, Saeki T, Dono R, Persico MG, Plowman GD et al. Differential expression of epidermal growth factor-related proteins in human colorectal tumors. Proc Natl Acad Sci USA 1991; 88: 7792–7796.
Maurer CA, Friess H, Kretschmann B, Zimmermann A, Stauffer A, Baer HU et al. Increased expression of erbB3 in colorectal cancer is associated with concomitant increase in the level of erbB2. Hum Pathol 1998; 29: 771–777.
Porebska I, Harlozinska A, Bojarowski T . Expression of the tyrosine kinase activity growth factor receptors (EGFR, ERB B2, ERB B3) in colorectal adenocarcinomas and adenomas. Tumour Biol 2000; 21: 105–115.
Kapitanovic S, Radosevic S, Slade N, Kapitanovic M, Andelinovic S, Ferencic Z et al. Expression of erbB-3 protein in colorectal adenocarcinoma: correlation with poor survival. J Cancer Res Clin Oncol 2000; 126: 205–211.
Lee JC, Wang ST, Chow NH, Yang HB . Investigation of the prognostic value of coexpressed erbB family members for the survival of colorectal cancer patients after curative surgery. Eur J Cancer 2002; 38: 1065–1071.
Kountourakis P, Pavlakis K, Psyrri A, Rontogianni D, Xiros N, Patsouris E et al. Prognostic significance of HER3 and HER4 protein expression in colorectal adenocarcinomas. BMC Cancer 2006; 6: 46.
Uner A, Ebinc FA, Akyurek N, Unsal D, Mentes BB, Dursun A . Vascular endothelial growth factor, c-erb-B2 and c-erb-B3 expression in colorectal adenoma and adenocarcinoma. Exp Oncol 2005; 27: 225–228.
Grivas PD, Antonacopoulou A, Tzelepi V, Sotiropoulou-Bonikou G, Kefalopoulou Z, Papavassiliou AG et al. HER-3 in colorectal tumourigenesis: from mRNA levels through protein status to clinicopathologic relationships. Eur J Cancer 2007; 43: 2602–2611.
Vadlamudi R, Mandal M, Adam L, Steinbach G, Mendelsohn J, Kumar R . Regulation of cyclooxygenase-2 pathway by HER2 receptor. Oncogene 1999; 18: 305–314.
Buck E, Eyzaguirre A, Haley JD, Gibson NW, Cagnoni P, Iwata KK . Inactivation of Akt by the epidermal growth factor receptor inhibitor erlotinib is mediated by HER-3 in pancreatic and colorectal tumor cell lines and contributes to erlotinib sensitivity. Mol Cancer Ther 2006; 5: 2051–2059.
Cho HJ, Kim WK, Kim EJ, Jung KC, Park S, Lee HS et al. Conjugated linoleic acid inhibits cell proliferation and ErbB3 signaling in HT-29 human colon cell line. Am J Physiol Gastrointest Liver Physiol 2003; 284: G996–G1005.
Lemoine NR, Lobresco M, Leung H, Barton C, Hughes CM, Prigent SA et al. The erbB-3 gene in human pancreatic cancer. J Pathol 1992; 168: 269–273.
Friess H, Yamanaka Y, Kobrin MS, Do DA, Buchler MW, Korc M . Enhanced erbB-3 expression in human pancreatic cancer correlates with tumor progression. Clin Cancer Res 1995; 1: 1413–1420.
Friess H, Wang L, Zhu Z, Gerber R, Schroder M, Fukuda A et al. Growth factor receptors are differentially expressed in cancers of the papilla of vater and pancreas. Ann Surg 1999; 230: 767–774.
Vaidya P, Kawarada Y, Higashiguchi T, Yoshida T, Sakakura T, Yatani R . Overexpression of different members of the type 1 growth factor receptor family and their association with cell proliferation in periampullary carcinoma. J Pathol 1996; 178: 140–145.
Dote H, Cerna D, Burgan WE, Camphausen K, Tofilon PJ . ErbB3 expression predicts tumor cell radiosensitization induced by Hsp90 inhibition. Cancer Res 2005; 65: 6967–6975.
Sanidas EE, Filipe MI, Linehan J, Lemoine NR, Gullick WJ, Rajkmuar T et al. Expression of the c-erbB-3 gene product in gastric cancer. Int J Cancer 1993; 54: 935–940.
Slesak B, Harlozinska A, Porebska I, Bojarowski T, Lapinska J, Rzeszutko M et al. Expression of epidermal growth factor receptor family proteins (EGFR, c-erbB-2, and c-erbB-3) in gastric cancer and chronic gastritis. Anticancer Res 1998; 18: 2727–2732.
Chausovsky A, Tsarfaty I, Kam Z, Yarden Y, Geiger B, Bershadsky AD . Morphogenetic effects of neuregulin (neu differentiation factor) in cultured epithelial cells. Mol Biol Cell 1998; 9: 3195–3209.
Kobayashi M, Iwamatsu A, Shinohara-Kanda A, Ihara S, Fukui Y . Activation of ErbB3-PI3-kinase pathway is correlated with malignant phenotypes of adenocarcinomas. Oncogene 2003; 22: 1294–1301.
Shintani S, Funayama T, Yoshihama Y, Alcalde RE, Matsumura T . Prognostic significance of ERBB3 overexpression in oral squamous cell carcinoma. Cancer Lett 1995; 95: 79–83.
Shintani S, Funayama T, Yoshihama Y, Alcalde RE, Ootsuki K, Terakado N et al. Expression of c-erbB family gene products in adenoid cystic carcinoma of salivary glands: an immunohistochemical study. Anticancer Res 1995; 15: 2623–2626.
Funayama T, Nakanishi T, Takahashi K, Taniguchi S, Takigawa M, Matsumura T . Overexpression of c-erbB-3 in various stages of human squamous cell carcinomas. Oncology 1998; 55: 161–167.
Xia W, Lau YK, Zhang HZ, Xiao FY, Johnston DA, Liu AR et al. Combination of EGFR, HER-2/neu, and HER-3 is a stronger predictor for the outcome of oral squamous cell carcinoma than any individual family member. Clin Cancer Res 1999; 5: 4164–4174.
Ibrahim SO, Vasstrand EN, Liavaag PG, Johannessen AC, Lillehaug JR . Expression of c-erbB proto-oncogene family members in squamous cell carcinoma of the head and neck. Anticancer Res 1997; 17: 4539–4546.
Sakurai K, Urade M, Takahashi Y, Kishimoto H, Noguchi K, Yasoshima H et al. Increased expression of c-erbB-3 protein and proliferating cell nuclear antigen during development of verrucous carcinoma of the oral mucosa. Cancer 2000; 89: 2597–2605.
Bei R, Pompa G, Vitolo D, Moriconi E, Ciocci L, Quaranta M et al. Co-localization of multiple ErbB receptors in stratified epithelium of oral squamous cell carcinoma. J Pathol 2001; 195: 343–348.
Ekberg T, Nestor M, Engstrom M, Nordgren H, Wester K, Carlsson J et al. Expression of EGFR, HER2, HER3, and HER4 in metastatic squamous cell carcinomas of the oral cavity and base of tongue. Int J Oncol 2005; 26: 1177–1185.
de Vicente JC, Esteban I, Germana P, Germana A, Vega JA . Expression of ErbB-3 and ErbB-4 protooncogene proteins in oral squamous cell carcinoma: a pilot study. Med Oral 2003; 8: 374–381.
Erjala K, Sundvall M, Junttila TT, Zhang N, Savisalo M, Mali P et al. Signaling via ErbB2 and ErbB3 associates with resistance and epidermal growth factor receptor (EGFR) amplification with sensitivity to EGFR inhibitor gefitinib in head and neck squamous cell carcinoma cells. Clin Cancer Res 2006; 12: 4103–4111.
Fluge O, Akslen LA, Haugen DR, Varhaug JE, Lillehaug JR . Expression of heregulins and associations with the ErbB family of tyrosine kinase receptors in papillary thyroid carcinomas. Int J Cancer 2000; 87: 763–770.
Kato S, Kobayashi T, Yamada K, Nishii K, Sawada H, Ishiguro H et al. Expression of erbB receptors mRNA in thyroid tissues. Biochim Biophys Acta 2004; 1673: 194–200.
Vairaktaris E, Goutzanis L, Vassiliou S, Spyridonidou S, Nkenke E, Papageorgiou G et al. Enhancement of erbB2 and erbB3 expression during oral oncogenesis in diabetic rats. J Cancer Res Clin Oncol 2008; 134: 337–344.
Friess H, Fukuda A, Tang WH, Eichenberger A, Furlan N, Zimmermann A et al. Concomitant analysis of the epidermal growth factor receptor family in esophageal cancer: overexpression of epidermal growth factor receptor mRNA but not of c-erbB-2 and c-erbB-3. World J Surg 1999; 23: 1010–1018.
Okano J, Gaslightwala I, Birnbaum MJ, Rustgi AK, Nakagawa H . Akt/protein kinase B isoforms are differentially regulated by epidermal growth factor stimulation. J Biol Chem 2000; 275: 30934–30942.
Taira N, Doihara H, Oota T, Hara F, Shien T, Takahashi H et al. Gefitinib, an epidermal growth factor receptor blockade agent, shows additional or synergistic effects on the radiosensitivity of esophageal cancer cells in vitro. Acta Med Okayama 2006; 60: 25–34.
Liu W, Zscheppang K, Murray S, Nielsen HC, Dammann CEL . The ErbB4 receptor in fetal rat lung fibroblasts and epithelial type II cells. Biochim Biophys Acta 2007; 1772: 737–747.
Patel NV, Acarregui MJ, Snyder JM, Klein JM, Sliwkowski MX, Kern JA . Neuregulin-1 and human epidermal growth factor receptors 2 and 3 play a role in human lung development in vitro. Am J Respir Cell Mol Biol 2000; 22: 432–440.
Sundaresan S, Roberts PE, King KL, Sliwkowski MX, Mather JP . Biological response to ErbB ligands in nontransformed cell lines correlates with a specific pattern of receptor expression. Endocrinology 1998; 139: 4756–4764.
Polosa R, Prosperini G, Leir SH, Holgate ST, Lackie PM, Davies DE . Expression of c-erbB receptors and ligands in human bronchial mucosa. Am J Respir Cell Mol Biol 1999; 20: 914–923.
Polosa R, Puddicombe SM, Krishna MT, Tuck AB, Howarth PH, Holgate ST et al. Expression of c-erbB receptors and ligands in the bronchial epithelium of asthmatic subjects. J Allergy Clin Immunol 2002; 109: 75–81.
O’Donnell RA, Richter A, Ward J, Angco G, Mehta A, Rousseau K et al. Expression of ErbB receptors and mucins in the airways of long term current smokers. Thorax 2004; 59: 1032–1040.
Vermeer PD, Einwalter LA, Moninger TO, Rokhlina T, Kern JA, Zabner J et al. Segregation of receptor and ligand regulates activation of epithelial growth factor receptor. Nature 2003; 422: 322–326.
Dammann CEL, Nielsen HC, Carraway KL . Role of neuregulin-1 beta in the developing lung. Am J Respir Crit Care Med 2003; 167: 1711–1716.
Vermeer PD, Panko L, Karp P, Lee JH, Zabner J . Differentiation of human airway epithelia is dependent on ErbB2. Am J Physiol Lung Cell Mol Physiol 2006; 291: L175–L180.
Nethery DE, Moore BB, Minowada G, Carroll J, Faress JA, Kern JA . Expression of mutant human epidermal receptor 3 attenuates lung fibrosis and improves survival in mice. J Appl Physiol 2005; 99: 298–307.
Faress JA, Nethery DE, Kern EF, Eisenberg R, Jacono FJ, Allen CL et al. Bleomycin induced pulmonary fibrosis is attenuated by a monoclonal antibody targeting HER2. J Appl Physiol 2007; 103: 2077–2083.
Ju CR, Xia XZ, Chen RC . Expressions of tumor necrosis factor-converting enzyme and ErbB3 in rats with chronic obstructive pulmonary disease. Chin Med J 2007; 120: 1505–1510.
Polosa R, Prosperini G, Tomaselli V, Howarth PH, Holgate ST, Davies DE . Expression of c-erbB receptors and ligands in human nasal epithelium. J Allergy Clin Immunol 2000; 106: 1124–1131.
Yi ES, Harclerode D, Gondo M, Stephenson M, Brown RW, Younes M et al. High c-erbB-3 protein expression is associated with shorter survival in advanced non-small cell lung carcinomas. Mod Pathol 1997; 10: 142–148.
Muller-Tidow C, Diederichs S, Bulk E, Pohle T, Steffen B, Schwable J et al. Identification of metastasis-associated receptor tyrosine kinases in non-small cell lung cancer. Cancer Res 2005; 65: 1778–1782.
Lai WW, Chen FF, Wu MH, Chow NH, Su WC, Ma MC et al. Immunohistochemical analysis of epidermal growth factor receptor family members in stage I non-small cell lung cancer. Ann Thorac Surg 2001; 72: 1868–1876.
Hilbe W, Dirnhofer S, Oberwasserlechner F, Eisterer W, Ammann K, Schmid T et al. Immunohistochemical typing of non-small cell lung cancer on cryostat sections: correlation with clinical parameters and prognosis. J Clin Pathol 2003; 56: 736–741.
Chen HY, Yu SL, Chen CH, Chang GC, Chen CY, Yuan A et al. A five-gene signature and clinical outcome in non-small-cell lung cancer. New Engl J Med 2007; 356: 11–20.
Zhou H, Liu L, Lee K, Qin X, Grasso AW, Kung HJ et al. Lung tumorigenesis associated with erb-B-2 and erb-B-3 overexpression in human erb-B-3 transgenic mice is enhanced by methylnitrosourea. Oncogene 2002; 21: 8732–8740.
Fujimoto N, Wislez M, Zhang J, Iwanaga K, Dackor J, Hanna AE et al. High expression of ErbB family members and their ligands in lung adenocarcinomas that are sensitive to inhibition of epidermal growth factor receptor. Cancer Res 2005; 65: 11478–11485.
Blons H, Cote JF, Le Corre D, Riquet M, Fabre-Guilevin E, Laurent-Puig P et al. Epidermal growth factor receptor mutation in lung cancer are linked to bronchioloalveolar differentiation. Am J Surg Pathol 2006; 30: 1309–1315.
Gorgoulis V, Sfikakis PP, Karameris A, Papastamatiou H, Trigidou R, Veslemes M et al. Molecular and immunohistochemical study of class I growth factor receptors in squamous cell lung carcinomas. Pathol Res Pract 1995; 191: 973–981.
Reinmuth N, Brandt B, Kunze WP, Junker K, Thomas M, Achatzy R et al. Ploidy, expression of erbB1, erbB2, P53 and amplification of erbB1, erbB2 and erbB3 in non-small cell lung cancer. Eur Respir J 2000; 16: 991–996.
Amann J, Kalyankrishna S, Massion PP, Ohm JE, Girard L, Shigematsu H et al. Aberrant epidermal growth factor receptor signaling and enhanced sensitivity to EGFR inhibitors in lung cancer. Cancer Res 2005; 65: 226–235.
Cappuzzo F, Toschi L, Domenichini I, Bartolini S, Ceresoli GL, Rossi E et al. HER3 genomic gain and sensitivity to gefitinib in advanced non-small-cell lung cancer patients. Br J Cancer 2005; 93: 1334–1340.
Al-Moustafa A, Alaoui-Jamali M, Paterson J, O’Connor-McCourt M . Expression of P185erbB-2, P160erbB-3, P180erbB-4, and heregulin α in human normal bronchial epithelial and lung cancer cell lines. Anticancer Res 1999; 19: 481–486.
Fernandes AM, Hamburger AW, Gerwin BI . Production of epidermal growth factor related ligands in tumorigenic and benign human lung epithelial cells. Cancer Lett 1999; 142: 55–63.
Gollamudi M, Nethery D, Liu J, Kern JA . Autocrine activation of ErbB2/ErbB3 receptor complex by NRG-1 in non-small cell lung cancer cell lines. Lung Cancer 2004; 43: 135–143.
Lee HY, Srinivas H, Xia D, Lu Y, Superty R, LaPushin R et al. Evidence that phosphatidylinositol 3-kinase- and mitogen-activated protein kinase kinase-4/c-Jun NH2-terminal kinase-dependent pathways cooperate to maintain lung cancer cell survival. J Biol Chem 2003; 278: 23630–23638.
Kurie JM . Role of protein kinase B-dependent signaling in lung tumorigenesis. Chest 2004; 125 (Suppl 5): 141S–144S.
Granville CA, Memmott RM, Gills JJ, Dennis PA . Handicapping the race to develop inhibitors of the phosphoinositide 3-kinase/Akt/mammalian target of rapamycin pathway. Clin Cancer Res 2006; 12: 679–689.
Tsurutani J, West KA, Sayyah J, Gills JJ, Dennis PA . Inhibition of the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin pathway but not the MEK/ERK pathway attenuates laminin-mediated small cell lung cancer cellular survival and resistance to imatinib mesylate or chemotherapy. Cancer Res 2005; 65: 8423–8432.
West KA, Linnoila IR, Belinsky SA, Harris CC, Dennis PA . Tobacco carcinogen-induced cellular transformation increases activation of the phosphatidylinositol 3′-kinase/Akt pathway in vitro and in vivo. Cancer Res 2004; 64: 446–451.
Tsurutani J, Castillo SS, Brognard J, Granville CA, Zhang C, Gills JJ et al. Tobacco components stimulate Akt-dependent proliferation and NF kappa B-dependent survival in lung cancer cells. Carcinogenesis 2005; 26: 1182–1195.
Johnson JI, Decker S, Zaharevitz D, Rubinstein LV, Venditti JM, Schepartz S et al. Relationships between drug activity in NCI preclinical in vitro and in vivo models and early clinical trials. Br J Cancer 2001; 84: 1424–1431.
Pao W, Miller V, Zakowski M, Doherty J, Politi K, Sarkaria I et al. EGF receptor gene mutations are common in lung cancers from ‘never smokers’ and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci USA 2004; 101: 13306–13311.
Paez JG, Janne PA, Lee JC, Tracy S, Greulich H, Gabriel S et al. EGFR mutations in lung cancer: correlations with clinical response to gefitinib therapy. Science 2004; 304: 1497–1500.
Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004; 350: 2129–2139.
Riely GJ, Politi KA, Miller VA, Pao W . Update on epidermal growth factor receptor mutations in non-small cell lung cancer. Clin Cancer Res 2006; 12: 7232–7241.
Edelman JM . An update on the role of epidermal growth factor receptor inhibitors in non-small cell lung cancer. Semin Oncol 2005; 32 (6 Suppl 10): S3–S8.
Haber DA, Bell DW, Sordella R, Kwak EL, Godin-Heymann N, Sharma SV et al. Molecular targeted therapy of lung cancer: EGFR mutations and response to EGFR inhibitors. Cold Spring Harb Symp Quant Biol 2005; 70: 419–426.
Tomizawa Y, Iijima H, Sunaga N, Sato K, Takise A, Otani Y et al. Clinicopathologic significance of the mutations of the epidermal growth factor receptor gene in patients with non-small cell lung cancer. Clin Cancer Res 2005; 11: 6816–6822.
Johnson BE, Janne PA . Epidermal growth factor receptor mutations in patients with non-small cell lung cancer. Cancer Res 2005; 65: 7525–7529.
Tam IY, Chung LP, Suen WS, Wang E, Wong MC, Ho KK et al. Distinct epidermal growth factor receptor and KRAS mutation patterns in non-small cell lung cancer patients with different tobacco exposure and clinicopathologic features. Clin Cancer Res 2006; 12: 1647–1653.
Shigematsu H, Gazdar AF . Somatic mutations of epidermal growth factor receptor signaling pathway in lung cancers. Int J Cancer 2006; 118: 257–262.
Cappuzzo F, Hirsch FR, Rossi E, Bartolini S, Ceresoli GL, Bemis L et al. Epidermal growth factor receptor gene and protein and gefitinib sensitivity in non-small-cell lung cancer. J Natl Cancer Inst 2005; 97: 634–655.
Dziadziuszko R, Witta SE, Cappuzzo F, Park S, Tanaka K, Danenberg PV et al. Epidermal growth factor receptor messenger RNA expression, gene dosage, and gefitinib sensitivity in non-small cell lung cancer. Clin Cancer Res 2006; 12: 3078–3084.
Dziadziuszko R, Hirsch FR, Varella-Garcia M, Bunn PA . Selecting lung cancer patients for treatment with epidermal growth factor receptor tyrosine kinase inhibitors by immunohistochemistry and fluorescence in situ hybridization—why, when, and how? Clin Cancer Res 2006; 12: 4409s–4415s.
Reinmuth N, Meister M, Muley T, Steins M, Kreuter M, Herth FJF et al. Molecular determinants of response to RTK-targeting agents in nonsmall cell lung cancer. Int J Cancer 2006; 119: 727–734.
Akca H, Tani M, Hishida T, Matsumoto S, Yokota J . Activation of the AKT and STAT3 pathways and prolonged survival by a mutant EGFR in human lung cancer cells. Lung Cancer 2006; 54: 25–33.
Giaccone G, Gallegos Ruiz M, Le Chevalier T, Thatcher N, Smit E, Rodriguez JA et al. Erlotinib for frontline treatment of advanced non-small cell lung cancer: a phase II study. Clin Cancer Res 2006; 12: 6049–6055.
Asahina H, Yamazaki K, Kinoshita I, Sukoh N, Harada M, Yokouchi H et al. A phase II trial of gefitinib as first-line therapy for advanced non-small cell lung cancer with epidermal growth factor receptor mutations. Br J Cancer 2006; 95: 998–1004.
Cappuzzo F, Varella-Garcia M, Shigematsu H, Domenichini I, Bartolini S, Ceresoli GL et al. Increased HER2 gene copy number is associated with response to gefitinib therapy in epidermal growth factor receptor-positive non-small-cell lung cancer patients. J Clin Oncol 2005; 23: 5007–5018.
Engelman JA, Cantley LC . The role of the ErbB family members in non-small cell lung cancers sensitive to epidermal growth factor receptor kinase inhibitors. Clin Cancer Res 2006; 12: 4372s–4376s.
Rosell R, Cecere F, Santarpia M, Reguart N, Taron M . Predicting the outcome of chemotherapy for lung cancer. Curr Opin Pharmacol 2006; 6: 323–331.
Ono M, Hirata A, Kometani T, Miyagawa M, Ueda S, Kinoshita H et al. Sensitivity to gefitinib (Iressa, ZD1839) in non-small cell lung cancer cell lines correlates with dependence on the epidermal growth factor (EGF) receptor/extracellular signal-regulated kinase 1/2 and EGF receptor/Akt pathway for proliferation. Mol Cancer Ther 2004; 3: 465–472.
Thomson S, Buck E, Petti F, Griffin G, Brown E, Ramnarine N et al. Epithelial to mesenchymal transition is a determinant of sensitivity of non-small-cell lung carcinoma cell lines and xenografts to epidermal growth factor receptor inhibition. Cancer Res 2005; 65: 9455–9462.
Sordella R, Bell DW, Haber DA, Settleman J . Gefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways. Science 2004; 305: 1163–1167.
Cappuzzo F, Magrini E, Ceresoli GL, Bartolini S, Rossi E, Ludovini V et al. Akt phosphorylation and gefitinib efficacy in patients with advanced non-small cell lung cancer. J Natl Cancer Inst 2004; 96: 1133–1141.
Engelman JA, Janne PA, Mermel C, Pearlberg J, Mukohara T, Fleet C et al. ErbB-3 mediates phosphoinositide 3-kinase activity in gefitinib-sensitive non-small cell lung cancer cell lines. Proc Natl Acad Sci USA 2005; 102: 3788–3793.
Janmaat ML, Rodriguez JA, Gallegos-Ruiz M, Kruyt FAE, Giaccone G . Enhanced cytotoxicity induced by gefitinib and specific inhibitors of the Ras or phosphatidyl inositol-3 kinase pathways in non-small cell lung cancer cells. Int J Cancer 2006; 118: 209–214.
Anido J, Matar P, Albanell J, Guzman M, Rojo F, Arribas J et al. ZD1839, a specific epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, induces the formation of inactive EGFR/HER2 and EGFR/HER3 heterodimers and prevents heregulin signaling in HER2-overexpressing breast cancer cells. Clin Cancer Res 2003; 9: 1274–1283.
Hirata A, Hosoi F, Miyagawa M, Ueda S, Naito S, Fujii T et al. HER2 overexpression increases sensitivity to gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, through inhibition of HER2/HER3 heterodimer formation in lung cancer cells. Cancer Res 2005; 65: 4253–4260.
Ihle NT, Paine-Murrieta G, Berggren MI, Baker A, Tate WR, Wipf P et al. The phosphatidylinositol-3-kinase inhibitor PX-866 overcomes resistance to the epidermal growth factor receptor inhibitor gefitinib in A-549 human non-small cell lung cancer xenografts. Mol Cancer Ther 2005; 4: 1349–1357.
Zhou BS, Fridman JS, Liu X, Friedman SM, Newton RC, Scherle PA . ADAM proteases, ErbB pathways and cancer. Expert Opin Investig Drugs 2005; 14: 591–606.
Zhou BS, Peyton M, He B, Liu C, Girard L, Caudler E et al. Targeting ADAM-mediated ligand cleavage to inhibit HER3 and EGFR pathways in non-small cell lung cancer. Cancer Cell 2006; 10: 39–50.
Sakai K, Yokote H, Murakami-Murofushi K, Tamura T, Saijo N, Nishio K . Pertuzumab, a novel HER dimerization inhibitor, inhibits the growth of human lung cancer cells mediated by the HER3 signaling pathway. Cancer Sci 2007; 98: 1498–1503.
Janmaat ML, Rodriguez JA, Jimeno J, Kruyt FAE, Giaccone G . Kahalalide F induces necrosis-like cell death that involves depletion of ErbB3 and inhibition of Akt signaling. Mol Pharmacol 2005; 68: 502–510.
Munster PN, Marchion DC, Basso AD, Rosen N . Degradation of HER2 by ansamycins induces growth arrest and apoptosis in cells with HER2 overexpression via a HER3, phosphatidylinositol 3′-kinase-AKT-dependent pathway. Cancer Res 2002; 62: 3132–3137.
Camphausen K, Tofilon PJ . Inhibition of Hsp90: a multitarget approach to radiosensitization. Clin Cancer Res 2007; 13: 4326–4330.
Chen CH, Chernis GA, Hoang VQ, Landgraf R . Inhibition of heregulin signaling by an aptamer that preferentially binds to the oligomeric form of human epidermal growth factor receptor-3. Proc Natl Acad Sci USA 2003; 100: 9226–9231.
Lund CV, Popkov M, Magnenat L, Barbas CF . Zinc finger transcription factors designed for bispecific coregulation of ErbB2 and ErbB3 receptors: insights into ErbB receptor biology. Mol Cell Biol 2005; 25: 9082–9091.
Samant GV, Sylvester PW . γ Tocotrienol inhibits ErbB3-dependent PI3K/Akt mitogammagenic signalling in neoplastic mammary epithelial cells. Cell Prolif 2006; 39: 563–574.
Scott GK, Goga A, Bhaumik D, Berger CE, Sullivan CS, Benz CC . Coordinate suppression of ERBB2 and ERBB3 by enforced expression of micro-RNA miR-125a or miR-125b. J Biol Chem 2007; 282: 1479–1486.
Sweeney C, Carraway KL . Negative regulation of ErbB family receptor tyrosine kinases. Br J Cancer 2004; 90: 289–293.
Menendez JA, Lupu R . Transphosphorylation of kinase-dead HER3 and breast cancer progression: a new standpoint or an old concept revisited? Breast Cancer Res 2007; 9: 111.
Hynes NE, Schlange T . Targeting ADAMS and ERBBs in lung cancer. Cancer Cell 2006; 10: 7–11.
Motoyama AB, Hynes NE, Lane HA . The efficacy of ErbB receptor-targeted anticancer therapeutics is influenced by the availability of epidermal growth factor-related peptides. Cancer Res 2002; 62: 3151–3158.
Acknowledgements
Thanks to Dr Gavin MacBeath and Dr Anne Hamburger for helpful comments and to Meghana Gupta for article review. This work was supported in part by the Intramural Research Program of the US NIH, National Cancer Institute. Also, this project has been funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract NO1-CO-12400. The content of this publication does not necessarily reflect the views or policy of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government.
Author information
Authors and Affiliations
Corresponding author
Additional information
All genes and proteins are named by the symbols designated by the Human Genome Organization (HUGO) Gene Nomenclature Committee. They are present in all capital letters, unless specified in reference to a rodent gene/protein. The protein sequence numbering for ERBB3 is based on that presented in the National Center for Biotechnology Information (NCBI) website for human ERBB3.
Rights and permissions
About this article
Cite this article
Sithanandam, G., Anderson, L. The ERBB3 receptor in cancer and cancer gene therapy. Cancer Gene Ther 15, 413–448 (2008). https://doi.org/10.1038/cgt.2008.15
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/cgt.2008.15
Keywords
This article is cited by
-
Exploring the Binding Mechanism of NRG1–ERBB3 Complex and Discovery of Potent Natural Products to Reduce Diabetes-Assisted Breast Cancer Progression
Interdisciplinary Sciences: Computational Life Sciences (2023)
-
Signaling pathways, microenvironment, and targeted treatments in Langerhans cell histiocytosis
Cell Communication and Signaling (2022)
-
Antibody–drug conjugates in solid tumors: a look into novel targets
Journal of Hematology & Oncology (2021)
-
The biology and rationale of targeting nectin-4 in urothelial carcinoma
Nature Reviews Urology (2021)
-
Making ERRFI1-Derived Peptides ‘Bindable’ to the Allosteric Dimerization Interface of Breast Cancer ERBB3 Kinase by Adding a Nonbonded Interaction System
International Journal of Peptide Research and Therapeutics (2021)
