erbb 3 receptor


Summary: A cell surface protein-tyrosine kinase receptor that is specific for NEUREGULINS. It has extensive homology to and can heterodimerize with the EGF RECEPTOR and the ERBB-2 RECEPTOR. Overexpression of the erbB-3 receptor is associated with TUMORIGENESIS.

Top Publications

  1. Camenisch T, Schroeder J, Bradley J, Klewer S, McDonald J. Heart-valve mesenchyme formation is dependent on hyaluronan-augmented activation of ErbB2-ErbB3 receptors. Nat Med. 2002;8:850-5 pubmed
    ..These data provide a link between extracellular matrix-hyaluronan and ErbB receptor activation during development of early heart-valve and septal mesenchyme. ..
  2. Sergina N, Rausch M, Wang D, Blair J, Hann B, Shokat K, et al. Escape from HER-family tyrosine kinase inhibitor therapy by the kinase-inactive HER3. Nature. 2007;445:437-41 pubmed
    ..The biologic marker with which to assess the efficacy of HER TKIs should be the transphosphorylation of HER3 rather than autophosphorylation. ..
  3. Frolov A, Schuller K, Tzeng C, Cannon E, Ku B, Howard J, et al. ErbB3 expression and dimerization with EGFR influence pancreatic cancer cell sensitivity to erlotinib. Cancer Biol Ther. 2007;6:548-54 pubmed
    ..Pancreatic cancer expression of ErbB3 may be useful for EGFR-targeted therapy patient selection. ..
  4. Citri A, Skaria K, Yarden Y. The deaf and the dumb: the biology of ErbB-2 and ErbB-3. Exp Cell Res. 2003;284:54-65 pubmed
    ..This review highlights recent structural insights into the mechanism of ligand-induced heterodimer formation, and concentrates on signaling pathways employed by ErbB-2 and ErbB-3 in normal and in malignant cells. ..
  5. Engelman J, Zejnullahu K, Mitsudomi T, Song Y, Hyland C, Park J, et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science. 2007;316:1039-43 pubmed
    ..Thus, we propose that MET amplification may promote drug resistance in other ERBB-driven cancers as well. ..
  6. Witton C, Reeves J, Going J, Cooke T, Bartlett J. Expression of the HER1-4 family of receptor tyrosine kinases in breast cancer. J Pathol. 2003;200:290-7 pubmed
    ..The development of HER-targeted agents (eg Herceptin, Iressa), and agents targeted at the downstream signalling pathways, therefore provides new possibilities in the treatment of breast cancer. ..
  7. 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;66:1418-26 pubmed
  8. Tovey S, Witton C, Bartlett J, Stanton P, Reeves J, Cooke T. Outcome and human epidermal growth factor receptor (HER) 1-4 status in invasive breast carcinomas with proliferation indices evaluated by bromodeoxyuridine labelling. Breast Cancer Res. 2004;6:R246-51 pubmed
    ..These results support the hypothesis that HER1-3 are associated with driving tumour proliferation, whereas HER4 is involved in a non-proliferative or even protective role. ..
  9. Ishizawar R, Miyake T, Parsons S. c-Src modulates ErbB2 and ErbB3 heterocomplex formation and function. Oncogene. 2007;26:3503-10 pubmed

More Information


  1. Erjala K, Sundvall M, Junttila T, 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;12:4103-11 pubmed
    ..ErbB2 and ErbB3 may have potential as predictive markers and as therapeutic targets for combination therapy in treatment of HNSCC with gefitinib. ..
  2. Funes M, Miller J, Lai C, Carraway K, Sweeney C. The mucin Muc4 potentiates neuregulin signaling by increasing the cell-surface populations of ErbB2 and ErbB3. J Biol Chem. 2006;281:19310-9 pubmed
  3. Shankaran H, Wiley H, Resat H. Modeling the effects of HER/ErbB1-3 coexpression on receptor dimerization and biological response. Biophys J. 2006;90:3993-4009 pubmed
    ..Results indicate that coexpression of EGFR with HER2 and HER3 at low to moderate levels may enable cells to match the response of a high HER2 expresser. ..
  4. Zaczek A, Wełnicka Jaśkiewicz M, Bielawski K, Jaskiewicz J, Badzio A, Olszewski W, et al. Gene copy numbers of HER family in breast cancer. J Cancer Res Clin Oncol. 2008;134:271-9 pubmed
    ..The aim of the study was to analyze the occurrence of abnormal gene copy numbers of all HER oncogenes and to correlate these alterations to other clinicopathological variables in a consecutive series of 225 breast cancer patients...
  5. Hutcheson I, Knowlden J, Hiscox S, Barrow D, Gee J, Robertson J, et al. Heregulin beta1 drives gefitinib-resistant growth and invasion in tamoxifen-resistant MCF-7 breast cancer cells. Breast Cancer Res. 2007;9:R50 pubmed
    ..This may have implications for the effectiveness of anti-EGFR therapies in breast cancer as HRGbeta1 is enriched in many EGFR-positive breast tumours. ..
  6. Lee Y, Cho S, Seo J, Shin B, Kim H, Kim I, et al. Correlated expression of erbB-3 with hormone receptor expression and favorable clinical outcome in invasive ductal carcinomas of the breast. Am J Clin Pathol. 2007;128:1041-9 pubmed
    ..In an era of personalized targeted therapy, erbB-3 expression and its coexpressive pattern with other EGFR family members could be an important determinant for therapeutic plans for breast cancer treatment. ..
  7. Smith B, Chin D, Maltzman W, Crosby K, Hortobagyi G, Bacus S. The efficacy of Herceptin therapies is influenced by the expression of other erbB receptors, their ligands and the activation of downstream signalling proteins. Br J Cancer. 2004;91:1190-4 pubmed
  8. Sithanandam G, Anderson L. The ERBB3 receptor in cancer and cancer gene therapy. Cancer Gene Ther. 2008;15:413-48 pubmed publisher
    ..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. ..
  9. Hume C, Kirkegaard M, Oesterle E. ErbB expression: the mouse inner ear and maturation of the mitogenic response to heregulin. J Assoc Res Otolaryngol. 2003;4:422-43 pubmed
    ..The distribution of erbBs in the neonatal and adult mouse ear is consistent with the EGF receptor/ligand family regulating diverse cellular processes in the inner ear, including cell proliferation and differentiation...
  10. Hudelist G, Singer C, Manavi M, Pischinger K, Kubista E, Czerwenka K. Co-expression of ErbB-family members in human breast cancer: Her-2/neu is the preferred dimerization candidate in nodal-positive tumors. Breast Cancer Res Treat. 2003;80:353-61 pubmed
    ..We have further shown that Her-2/neu is the preferred co-expression partner in nodal-positive tumors and thus the most likely dimerization candidate in malignant breast tumors. ..
  11. 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;9:1274-83 pubmed
    ..Our findings suggest that there is a strong rationale to conduct clinical trials of ZD1839 in patients with HER2-overexpressing breast tumors. ..
  12. Vakar Lopez F, Cheng C, Kim J, Shi G, Troncoso P, Tu S, et al. Up-regulation of MDA-BF-1, a secreted isoform of ErbB3, in metastatic prostate cancer cells and activated osteoblasts in bone marrow. J Pathol. 2004;203:688-95 pubmed
    ..These observations indicate that MDA-BF-1 is up-regulated in metastatic PCa and raise the interesting possibility that MDA-BF-1 may play a role in the metastasis and progression of PCa, particularly in bone. ..
  13. Ferrer Soler L, Vazquez Martin A, Brunet J, Menendez J, 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 pubmed
  14. Jackson Fisher A, Bellinger G, Breindel J, Tavassoli F, Booth C, Duong J, et al. ErbB3 is required for ductal morphogenesis in the mouse mammary gland. Breast Cancer Res. 2008;10:R96 pubmed publisher
    ..Proliferation rates were not affected by the lack of ErbB3, but there was an increase in apoptosis in ErbB3-/- terminal end buds. Endogenous ErbB3 regulates morphogenesis of mammary epithelium. ..
  15. Lee Hoeflich S, Crocker L, Yao E, Pham T, Munroe X, Hoeflich K, et al. A central role for HER3 in HER2-amplified breast cancer: implications for targeted therapy. Cancer Res. 2008;68:5878-87 pubmed publisher
  16. Engelman J, Mukohara T, Zejnullahu K, Lifshits E, Borras A, Gale C, et al. Allelic dilution obscures detection of a biologically significant resistance mutation in EGFR-amplified lung cancer. J Clin Invest. 2006;116:2695-706 pubmed
  17. Schulze W, Deng L, Mann M. Phosphotyrosine interactome of the ErbB-receptor kinase family. Mol Syst Biol. 2005;1:2005.0008 pubmed
    ..Our results demonstrate that system-wide mapping of peptide-protein interactions sites is possible, and suggest shared and unique roles of ErbB-receptor family members in downstream signaling. ..
  18. Stern D. ERBB3/HER3 and ERBB2/HER2 duet in mammary development and breast cancer. J Mammary Gland Biol Neoplasia. 2008;13:215-23 pubmed publisher
  19. Holbro T, Beerli R, Maurer F, Koziczak M, Barbas C, Hynes N. The ErbB2/ErbB3 heterodimer functions as an oncogenic unit: ErbB2 requires ErbB3 to drive breast tumor cell proliferation. Proc Natl Acad Sci U S A. 2003;100:8933-8 pubmed
    ..Furthermore, we identify ErbB3's role, which is to couple active ErbB2 to the phosphatidylinositol 3-kinase/protein kinase B pathway. Thus, the ErbB2/ErbB3 dimer functions as an oncogenic unit to drive breast tumor cell proliferation. ..
  20. Zhang Y, Wang X, Jelovac D, Nakanishi T, Yu M, Akinmade D, et al. The ErbB3-binding protein Ebp1 suppresses androgen receptor-mediated gene transcription and tumorigenesis of prostate cancer cells. Proc Natl Acad Sci U S A. 2005;102:9890-5 pubmed
    ..These findings suggest that Ebp1 is a previously unrecognized therapeutic target for treatment of hormone refractory prostate cancer. ..
  21. Lammering G, Hewit T, Valerie K, Lin P, Contessa J, Schmidt Ullrich R. Anti-erbB receptor strategy as a gene therapeutic intervention to improve radiotherapy in malignant human tumours. Int J Radiat Biol. 2003;79:561-8 pubmed
  22. Abd El Rehim D, Pinder S, Paish C, Bell J, Rampaul R, Blamey R, et al. Expression and co-expression of the members of the epidermal growth factor receptor (EGFR) family in invasive breast carcinoma. Br J Cancer. 2004;91:1532-42 pubmed
    ..These data imply that the combined profile expression patterns of the four receptor family members together provide more accurate information on the tumour behaviour than studying the expression of each receptor individually. ..
  23. Laederich M, Funes Duran M, Yen L, Ingalla E, Wu X, Carraway K, et al. The leucine-rich repeat protein LRIG1 is a negative regulator of ErbB family receptor tyrosine kinases. J Biol Chem. 2004;279:47050-6 pubmed
  24. 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;98:1498-503 pubmed
    ..The present results suggest that pertuzumab is effective against HRG-alpha-dependent cell growth in lung cancer cells through inhibition of HRG-alpha-stimulated HER2/HER3 signaling. ..
  25. Guix M, Faber A, Wang S, Olivares M, Song Y, Qu S, et al. Acquired resistance to EGFR tyrosine kinase inhibitors in cancer cells is mediated by loss of IGF-binding proteins. J Clin Invest. 2008;118:2609-19 pubmed publisher
    ..Moreover, combined therapeutic inhibition of EGFR and IGFIR may abrogate this acquired mechanism of drug resistance and is thus worthy of prospective clinical investigation. ..
  26. Honjo Y, Kniss J, Eisen J. Neuregulin-mediated ErbB3 signaling is required for formation of zebrafish dorsal root ganglion neurons. Development. 2008;135:2615-25 pubmed publisher
    ..Together, our results suggest that ErbB3 signaling is required for normal migration of trunk, but not cranial, neural crest cells. ..
  27. Cho H, Leahy D. Structure of the extracellular region of HER3 reveals an interdomain tether. Science. 2002;297:1330-3 pubmed
    ..These results also suggest new therapeutic approaches to modulating the behavior of members of the EGFR family. ..
  28. 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 pubmed
    ..HER-4 expression status may identify tumors with aggressive biological behavior and increased metastatic potential. ..
  29. Garrett T, McKern N, Lou M, Elleman T, Adams T, Lovrecz G, 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 pubmed
    ..Together, the data suggest a model in which ErbB2 is already in the activated conformation and ready to interact with other ligand-activated ErbB receptors. ..
  30. Revillion F, Pawlowski V, Lhotellier V, Louchez M, Peyrat J. 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;23:1455-60 pubmed
    ..In MCF-7 cells, we demonstrate that c-erbB-4 is down-regulated by estradiol and up-regulated by 4-OH tamoxifen, and confirm that the three other receptors followed the same pattern of expression. ..
  31. Yen L, Cao Z, Wu X, Ingalla E, Baron C, Young L, et al. Loss of Nrdp1 enhances ErbB2/ErbB3-dependent breast tumor cell growth. Cancer Res. 2006;66:11279-86 pubmed
    ..Our observations suggest that Nrdp1-mediated ErbB3 degradation suppresses cellular growth and motility, and that Nrdp1 loss in breast tumors may promote tumor progression by augmenting ErbB2/ErbB3 signaling. ..
  32. Junttila T, Akita R, Parsons K, Fields C, Lewis Phillips G, Friedman L, et al. Ligand-independent HER2/HER3/PI3K complex is disrupted by trastuzumab and is effectively inhibited by the PI3K inhibitor GDC-0941. Cancer Cell. 2009;15:429-40 pubmed publisher
    ..A selective and potent PI3K inhibitor, GDC-0941, is highly efficacious both in combination with trastuzumab and in the treatment of trastuzumab-resistant cells and tumors. ..
  33. Tovey S, Dunne B, Witton C, Forsyth A, Cooke T, Bartlett J. Can molecular markers predict when to implement treatment with aromatase inhibitors in invasive breast cancer?. Clin Cancer Res. 2005;11:4835-42 pubmed
  34. Folgiero V, Avetrani P, Bon G, Di Carlo S, Fabi A, Nisticò C, et al. Induction of ErbB-3 expression by alpha6beta4 integrin contributes to tamoxifen resistance in ERbeta1-negative breast carcinomas. PLoS ONE. 2008;3:e1592 pubmed publisher
  35. Memon A, Sorensen B, Melgard P, Fokdal L, Thykjaer T, Nexo E. Expression of HER3, HER4 and their ligand heregulin-4 is associated with better survival in bladder cancer patients. Br J Cancer. 2004;91:2034-41 pubmed
    ..While it is well established that an increased signalling through HER1 and HER2 is related to a poor prognosis, our data suggest that signalling through HER3 and HER4 is related to a favourable outcome in bladder cancer patients. ..
  36. Duneau J, Vegh A, Sturgis J. A dimerization hierarchy in the transmembrane domains of the HER receptor family. Biochemistry. 2007;46:2010-9 pubmed
    ..The correlation we observe between transmembrane domain and whole receptor interaction hierarchies opens a new perspective, suggesting a role for transmembrane receptor domains in the modulation of receptor signaling. ..
  37. Reschke M, Mihic Probst D, van der Horst E, Knyazev P, Wild P, Hutterer M, et al. HER3 is a determinant for poor prognosis in melanoma. Clin Cancer Res. 2008;14:5188-97 pubmed publisher
    ..Our results provide novel insights into the role of HER3 in melanoma and point out new possibilities for therapeutic intervention. ..
  38. Hamburger A. The role of ErbB3 and its binding partners in breast cancer progression and resistance to hormone and tyrosine kinase directed therapies. J Mammary Gland Biol Neoplasia. 2008;13:225-33 pubmed publisher
    ..These studies point to the importance of the evaluation of protein levels and functional activity of ErbB3 and its binding proteins in breast cancer prognosis and prediction of clinical response to treatment. ..
  39. Zhang Y, Hamburger A. Heregulin regulates the ability of the ErbB3-binding protein Ebp1 to bind E2F promoter elements and repress E2F-mediated transcription. J Biol Chem. 2004;279:26126-33 pubmed
    ..Our findings suggest that Ebp1, by linking HRG activation of membrane receptors to E2F gene activity, may be a downstream modulator of the effects of HRG on cell cycle progression. ..
  40. Sassen A, Rochon J, Wild P, Hartmann A, Hofstaedter F, Schwarz S, et al. Cytogenetic analysis of HER1/EGFR, HER2, HER3 and HER4 in 278 breast cancer patients. Breast Cancer Res. 2008;10:R2 pubmed publisher
    ..However, the clinical outcome with regard to total HER receptor state remains largely unknown...
  41. Wang L, Schulz T, Sherrer E, Dauphin D, Shin S, Nelson A, et al. Self-renewal of human embryonic stem cells requires insulin-like growth factor-1 receptor and ERBB2 receptor signaling. Blood. 2007;110:4111-9 pubmed
    ..These studies identify previously unappreciated RTKs that support hESC proliferation and self-renewal, and provide a rationally designed medium for the growth and maintenance of pluripotent hESCs. ..
  42. Qu S, Rinehart C, Wu H, Wang S, Carter B, Xin H, et al. Gene targeting of ErbB3 using a Cre-mediated unidirectional DNA inversion strategy. Genesis. 2006;44:477-86 pubmed
    ..Unidirectional DNA inversion by in vivo recombination is an effective strategy for targeted or ubiquitous gene knockout. ..
  43. Cai Z, Zhang G, Zhou Z, Bembas K, Drebin J, Greene M, et al. Differential binding patterns of monoclonal antibody 2C4 to the ErbB3-p185her2/neu and the EGFR-p185her2/neu complexes. Oncogene. 2008;27:3870-4 pubmed publisher
  44. Yang S, Raymond Stintz M, Ying W, Zhang J, Lidke D, Steinberg S, et al. Mapping ErbB receptors on breast cancer cell membranes during signal transduction. J Cell Sci. 2007;120:2763-73 pubmed
    ..These data suggest that the distinct topography of receptors and their docking partners modulates signaling activities. ..
  45. Xia W, Bisi J, Strum J, Liu L, Carrick K, Graham K, et al. Regulation of survivin by ErbB2 signaling: therapeutic implications for ErbB2-overexpressing breast cancers. Cancer Res. 2006;66:1640-7 pubmed
    ..These findings shed new light on the mechanism by which ErbB2 overexpression protects against apoptotic stimuli in breast cancer and identifies therapeutic interventions to improve clinical outcomes in these aggressive tumors. ..
  46. Yen L, Benlimame N, Nie Z, Xiao D, Wang T, Al Moustafa A, et al. Differential regulation of tumor angiogenesis by distinct ErbB homo- and heterodimers. Mol Biol Cell. 2002;13:4029-44 pubmed
    ..These results emphasize the biological implications of cell signaling diversity among members of the ErbB receptor family in regulation of the tumor microenvironment. ..
  47. Burgess A. EGFR family: structure physiology signalling and therapeutic targets. Growth Factors. 2008;26:263-74 pubmed publisher
    ..EGFR and erbB2 are frequently activated, over expressed or mutated in many common cancers and the antagonists and/or inhibitors of EGFR and/or erbB2 signalling have already been shown to have therapeutic benefits for cancer patients. ..
  48. Koutras A, Kalogeras K, Dimopoulos M, Wirtz R, Dafni U, Briasoulis E, et al. Evaluation of the prognostic and predictive value of HER family mRNA expression in high-risk early breast cancer: a Hellenic Cooperative Oncology Group (HeCOG) study. Br J Cancer. 2008;99:1775-85 pubmed publisher
    ..However, HER2 mRNA expression did not predict clinical benefit from paclitaxel. Kinetic RT-PCR represents an alternative method for evaluating the expression of HER family members in FFPE breast carcinomas. ..
  49. Agus D, Akita R, Fox W, Lewis G, Higgins B, Pisacane P, et al. Targeting ligand-activated ErbB2 signaling inhibits breast and prostate tumor growth. Cancer Cell. 2002;2:127-37 pubmed
    ..We demonstrate that the in vitro and in vivo growth of several breast and prostate tumor models is inhibited by 2C4 treatment. ..
  50. Wiseman S, Makretsov N, Nielsen T, Gilks B, Yorida E, Cheang M, et al. Coexpression of the type 1 growth factor receptor family members HER-1, HER-2, and HER-3 has a synergistic negative prognostic effect on breast carcinoma survival. Cancer. 2005;103:1770-7 pubmed
    ..Thus, coexpression of T1GFR family members identified a subset of patients with a poor disease prognosis who may potentially benefit from therapy simultaneously targeting several T1GFR family members. ..
  51. 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;26:1177-85 pubmed
    ..g. using radiolabelled antibodies or ligands, and EGFR seemed suitable as target since the expression was high, membrane associated and similar in the primary tumours and the corresponding metastases. ..
  52. Nagy P, Vereb G, Sebestyen Z, Horvath G, Lockett S, 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;115:4251-62 pubmed
    ..We conclude that local densities of ErbB2 and ErbB3, as well as the lipid environment profoundly influence the association properties and biological function of ErbB2. ..
  53. Jung J, Chung E, Seon M, Shin H, Kim E, Lim S, et al. Isoliquiritigenin (ISL) inhibits ErbB3 signaling in prostate cancer cells. Biofactors. 2006;28:159-68 pubmed
    ..These results indicate that ISL inhibits the proliferation of prostate cancer cells, at least in part, via the inhibition of ErbB3 signaling and the PI3K/Akt pathway. ..