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Role of ErbB4 in Breast Cancer

  • Maria Sundvall
  • Kristiina Iljin
  • Sami Kilpinen
  • Henri Sara
  • Olli-Pekka Kallioniemi
  • Klaus EleniusEmail author
Article

Abstract

Members of the ErbB subfamily of receptor tyrosine kinases are important regulators of normal mammary gland physiology, and aberrations in their signaling have been associated with breast tumorigenesis. Therapeutics targeting epidermal growth factor receptor (EGFR = ErbB1) or ErbB2 in breast cancer have been approved for clinical use. In contrast, relatively little is known about the biological significance of ErbB4 signaling in breast cancer. This review focuses on recent advances in our understanding about the role of ErbB4 in breast carcinogenesis, as well as in the potential clinical relevance of ErbB4 in breast cancer prognostics and therapy.

Keywords

Alternative splicing Epidermal growth factor Estrogen receptor HER4 Neuregulins Targeted therapeutics 

Abbreviations

HER

human epidermal growth factor receptor

EGFR

epidermal growth factor receptor

ER

estrogen receptor

PgR

progesterone receptor

NRG

neuregulin

TACE

tumor necrosis factor-α converting enzyme

IHC

immunohistochemistry

RT-PCR

reverse transcription-polymerase chain reaction

Notes

Acknowledgements

The authors would like to warmly acknowledge the efforts of the International Genomics Consortium’s (IGC) Expression Project for Oncology (expO) for generation of some of the breast cancer data utilized in this study. Work in authors’ laboratories has been supported by Academy of Finland, EU-EPITRON (LSHC-CT-2005-518417), Finnish Cancer Organizations, Marie Curie Canceromics (MEXT-CT-2003-2728), and Sigrid Juselius Foundation.

References

  1. 1.
    Hynes NE, Lane HA. ERBB receptors and cancer: the complexity of targeted inhibitors. Nat Rev Cancer 2005;5(5):341–54.PubMedCrossRefGoogle Scholar
  2. 2.
    Gschwind A, Fischer OM, Ullrich A. The discovery of receptor tyrosine kinases: targets for cancer therapy. Nat Rev Cancer 2004;4(5):361–70.PubMedCrossRefGoogle Scholar
  3. 3.
    Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 1987;235(4785):177–82.PubMedCrossRefGoogle Scholar
  4. 4.
    Revillion F, Bonneterre J, Peyrat JP. ERBB2 oncogene in human breast cancer and its clinical significance. Eur J Cancer 1998;34(6):791–808.PubMedCrossRefGoogle Scholar
  5. 5.
    Chan SK, Hill ME, Gullick WJ. The role of the epidermal growth factor receptor in breast cancer. J Mammary Gland Biol Neoplasia 2006;11(1):3–11.PubMedCrossRefGoogle Scholar
  6. 6.
    Gullick WJ. c-erbB-4/HER4: friend or foe? J Pathol 2003;200(3):279–81.PubMedCrossRefGoogle Scholar
  7. 7.
    Junttila TT, Sundvall M, Maatta JA, Elenius K. Erbb4 and its isoforms: selective regulation of growth factor responses by naturally occurring receptor variants. Trends Cardiovasc Med 2000;10(7):304–10.PubMedCrossRefGoogle Scholar
  8. 8.
    Paatero I, Elenius K. ErbB4 and its isoforms: patentable drug targets? Recent Patents on DNA & Gene Sequences 2008;2:27–33.Google Scholar
  9. 9.
    Stern DF. ERBB3/HER3 and ERBB2/HER2 duet in mammary development and breast cancer. J Mammary Gland Biol Neoplasia 2008. DOI  10.1007/s10911-008-9083-7.
  10. 10.
    Hamburger AW. 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. DOI  10.1007/s10911-008-9077-5.
  11. 11.
    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 U S A 1993;90(5):1746–50.PubMedCrossRefGoogle Scholar
  12. 12.
    Elenius K, Paul S, Allison G, Sun J, Klagsbrun M. Activation of HER4 by heparin-binding EGF-like growth factor stimulates chemotaxis but not proliferation. EMBO J 1997;16(6):1268–78.PubMedCrossRefGoogle Scholar
  13. 13.
    Riese DJ 2nd, Bermingham Y, van Raaij TM, Buckley S, Plowman GD, Stern DF. Betacellulin activates the epidermal growth factor receptor and erbB-4, and induces cellular response patterns distinct from those stimulated by epidermal growth factor or neuregulin-beta. Oncogene 1996;12(2):345–53.PubMedGoogle Scholar
  14. 14.
    Komurasaki T, Toyoda H, Uchida D, Morimoto S. Epiregulin binds to epidermal growth factor receptor and ErbB-4 and induces tyrosine phosphorylation of epidermal growth factor receptor, ErbB-2, ErbB-3 and ErbB-4. Oncogene 1997;15(23):2841–8.PubMedCrossRefGoogle Scholar
  15. 15.
    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(17):2681–9.PubMedCrossRefGoogle Scholar
  16. 16.
    Plowman GD, Green JM, Culouscou JM, Carlton GW, Rothwell VM, Buckley S. Heregulin induces tyrosine phosphorylation of HER4/p180erbB4. Nature 1993;366(6454):473–5.PubMedCrossRefGoogle Scholar
  17. 17.
    Carraway KL 3rd, Weber JL, Unger MJ, Ledesma J, Yu N, Gassmann M, et al. Neuregulin-2, a new ligand of ErbB3/ErbB4-receptor tyrosine kinases. Nature 1997;387(6632):512–6.PubMedCrossRefGoogle Scholar
  18. 18.
    Zhang D, Sliwkowski MX, Mark M, Frantz G, Akita R, Sun Y, et al. Neuregulin-3 (NRG3): a novel neural tissue-enriched protein that binds and activates ErbB4. Proc Natl Acad Sci U S A 1997;94(18):9562–7.PubMedCrossRefGoogle Scholar
  19. 19.
    Riese DJ 2nd, Stern DF. Specificity within the EGF family/ErbB receptor family signaling network. Bioessays 1998;20(1):41–8.PubMedCrossRefGoogle Scholar
  20. 20.
    Carpenter G. ErbB-4: mechanism of action and biology. Exp Cell Res 2003;284(1):66–77.PubMedCrossRefGoogle Scholar
  21. 21.
    Kainulainen V, Sundvall M, Maatta JA, Santiestevan E, Klagsbrun M, Elenius K. A natural ErbB4 isoform that does not activate phosphoinositide 3-kinase mediates proliferation but not survival or chemotaxis. J Biol Chem 2000;275(12):8641–9.PubMedCrossRefGoogle Scholar
  22. 22.
    Ni CY, Murphy MP, Golde TE, Carpenter G. gamma-Secretase cleavage and nuclear localization of ErbB-4 receptor tyrosine kinase. Science 2001;294(5549):2179–81.PubMedCrossRefGoogle Scholar
  23. 23.
    Lee HJ, Jung KM, Huang YZ, Bennett LB, Lee JS, Mei L, et al. Presenilin-dependent gamma-secretase-like intramembrane cleavage of ErbB4. J Biol Chem 2002;277(8):6318–23.PubMedCrossRefGoogle Scholar
  24. 24.
    Jones F. HER4 intracellular domain (4ICD) activity in the developing mammary gland and breast cancer. J Mammary Gland Biol Neoplasia 2008. DOI  10.1007/s10911-008-9076-6.
  25. 25.
    Aqeilan RI, Donati V, Palamarchuk A, Trapasso F, Kaou M, Pekarsky Y, et al. WW domain-containing proteins, WWOX and YAP, compete for interaction with ErbB-4 and modulate its transcriptional function. Cancer Res 2005;65(15):6764–72.PubMedCrossRefGoogle Scholar
  26. 26.
    Aqeilan RI, Donati V, Gaudio E, Nicoloso MS, Sundvall M, Korhonen A, et al. Association of Wwox with ErbB4 in breast cancer. Cancer Res 2007;67(19):9330–6.PubMedCrossRefGoogle Scholar
  27. 27.
    Omerovic J, Santangelo L, Puggioni EM, Marrocco J, Dall’Armi C, Palumbo C, et al. The E3 ligase Aip4/Itch ubiquitinates and targets ErbB-4 for degradation. FASEB J 2007;21(11):2849–62.PubMedCrossRefGoogle Scholar
  28. 28.
    Sundvall M, Korhonen A, Paatero I, Gaudio E, Melino G, Croce CM, Aqeilan RI, Elenius K. Isoform-specific monoubiquitination, endocytosis, and degradation of alternatively spliced ErbB4 isoforms. Proc Natl Acad Sci U S A 2008;105(11):4162–7.PubMedCrossRefGoogle Scholar
  29. 29.
    Junttila TT, Sundvall M, Lundin M, Lundin J, Tanner M, Harkonen P, et al. Cleavable ErbB4 isoform in estrogen receptor-regulated growth of breast cancer cells. Cancer Res 2005;65(4):1384–93.PubMedCrossRefGoogle Scholar
  30. 30.
    Maatta JA, Sundvall M, Junttila TT, Peri L, Laine VJ, Isola J, et al. Proteolytic cleavage and phosphorylation of a tumor-associated ErbB4 isoform promote ligand-independent survival and cancer cell growth. Mol Biol Cell 2006;17(1):67–79.PubMedCrossRefGoogle Scholar
  31. 31.
    Lynch CC, Vargo-Gogola T, Martin MD, Fingleton B, Crawford HC, Matrisian LM. Matrix metalloproteinase 7 mediates mammary epithelial cell tumorigenesis through the ErbB4 receptor. Cancer Res 2007;67(14):6760–7.PubMedCrossRefGoogle Scholar
  32. 32.
    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 paired combinations of ErbB receptors. Cancer Res 2003;63(13):3764–74.PubMedGoogle Scholar
  33. 33.
    Cohen BD, Kiener PA, Green JM, Foy L, Fell HP, Zhang K. The relationship between human epidermal growth-like factor receptor expression and cellular transformation in NIH3T3 cells. J Biol Chem 1996;271(48):30897–903.PubMedCrossRefGoogle Scholar
  34. 34.
    Zhu Y, Sullivan LL, Nair SS, Williams CC, Pandey AK, Marrero L, et al. Coregulation of estrogen receptor by ERBB4/HER4 establishes a growth-promoting autocrine signal in breast tumor cells. Cancer Res 2006;66(16):7991–8.PubMedCrossRefGoogle Scholar
  35. 35.
    Tang CK, Concepcion XZ, Milan M, Gong X, Montgomery E, Lippman ME. Ribozyme-mediated down-regulation of ErbB-4 in estrogen receptor-positive breast cancer cells inhibits proliferation both in vitro and in vivo. Cancer Res 1999;59(20):5315–22.PubMedGoogle Scholar
  36. 36.
    Muraoka-Cook RS, Caskey LS, Sandahl MA, Hunter DM, Husted C, Strunk KE, et al. Heregulin-dependent delay in mitotic progression requires HER4 and BRCA1. Mol Cell Biol 2006;26(17):6412–24.PubMedCrossRefGoogle Scholar
  37. 37.
    Sartor CI, Zhou H, Kozlowska E, Guttridge K, Kawata E, Caskey L, et al. Her4 mediates ligand-dependent antiproliferative and differentiation responses in human breast cancer cells. Mol Cell Biol 2001;21(13):4265–75.PubMedCrossRefGoogle Scholar
  38. 38.
    Chen X, Levkowitz G, Tzahar E, Karunagaran D, Lavi S, Ben-Baruch N, et al. An immunological approach reveals biological differences between the two NDF/heregulin receptors, ErbB-3 and ErbB-4. J Biol Chem 1996;271(13):7620–9.PubMedCrossRefGoogle Scholar
  39. 39.
    Peles E, Bacus SS, Koski RA, Lu HS, Wen D, Ogden SG, et al. Isolation of the neu/HER-2 stimulatory ligand: a 44 kD glycoprotein that induces differentiation of mammary tumor cells. Cell 1992;69(1):205–16.PubMedCrossRefGoogle Scholar
  40. 40.
    Muraoka-Cook RS, Sandahl M, Husted C, Hunter D, Miraglia L, Feng SM, et al. The intracellular domain of ErbB4 induces differentiation of mammary epithelial cells. Mol Biol Cell 2006;17(9):4118–29.PubMedCrossRefGoogle Scholar
  41. 41.
    Naresh A, Long W, Vidal GA, Wimley WC, Marrero L, Sartor CI, et al. The ERBB4/HER4 intracellular domain 4ICD is a BH3-only protein promoting apoptosis of breast cancer cells. Cancer Res 2006;66(12):6412–20.PubMedCrossRefGoogle Scholar
  42. 42.
    Arasada RR, Carpenter G. Secretase-dependent tyrosine phosphorylation of Mdm2 by the ErbB-4 intracellular domain fragment. J Biol Chem 2005;280(35):30783–7.PubMedCrossRefGoogle Scholar
  43. 43.
    Muraoka-Cook RS, Feng S-M, Strunk KE, Earp III HS. ErbB4/HER4: role in mammary gland development, differentiation and growth inhibition. J Mammary Gland Biol Neoplasia 2008. DOI  10.1007/s10911-008-9080-x.
  44. 44.
    Howard BA. The role of NRG3 in mammary development. J Mammary Gland Biol Neoplasia 2008. DOI  10.1007/s10911-008-9082-8.
  45. 45.
    McBryan J, Howlin J, Napoletano S, Martin F. Amphiregulin: role in mammary gland development and breast cancer. J Mammary Gland Biol Neoplasia 2008. DOI  10.1007/s10911-008-9075-7.
  46. 46.
    Sternlicht MD, Sunnarborg SW. The ADAM17-amphiregulin-EGFR axis in mammary development and cancer. J Mammary Gland Biol Neoplasia 2008. DOI  10.1007/s10911-008-9084-6.
  47. 47.
    Tidcombe H, Jackson-Fisher A, Mathers K, Stern DF, Gassmann M, Golding JP. Neural and mammary gland defects in ErbB4 knockout mice genetically rescued from embryonic lethality. Proc Natl Acad Sci U S A 2003;100(14):8281–6.PubMedCrossRefGoogle Scholar
  48. 48.
    Long W, Wagner KU, Lloyd KC, Binart N, Shillingford JM, Hennighausen L, et al. Impaired differentiation and lactational failure of Erbb4-deficient mammary glands identify ERBB4 as an obligate mediator of STAT5. Development 2003;130(21):5257–68.PubMedCrossRefGoogle Scholar
  49. 49.
    Jackson-Fisher AJ, Bellinger G, Shum E, Duong JK, Perkins AS, Gassmann M, et al. Formation of Neu/ErbB2-induced mammary tumors is unaffected by loss of ErbB4. Oncogene 2006;25(41):5664–72.PubMedCrossRefGoogle Scholar
  50. 50.
    Libermann TA, Nusbaum HR, Razon N, Kris R, Lax I, Soreq H, et al. Amplification, enhanced expression and possible rearrangement of EGF receptor gene in primary human brain tumours of glial origin. Nature 1985;313(5998):144–7.PubMedCrossRefGoogle Scholar
  51. 51.
    Ekstrand AJ, Sugawa N, James CD, Collins VP. Amplified and rearranged epidermal growth factor receptor genes in human glioblastomas reveal deletions of sequences encoding portions of the N- and/or C-terminal tails. Proc Natl Acad Sci U S A 1992;89(10):4309–13.PubMedCrossRefGoogle Scholar
  52. 52.
    Vogt U, Bielawski K, Schlotter CM, Bosse U, Falkiewicz B, Podhajska AJ. Amplification of erbB-4 oncogene occurs less frequently than that of erbB-2 in primary human breast cancer. Gene 1998;223(1–2):375–80.PubMedCrossRefGoogle Scholar
  53. 53.
    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(1):R2.PubMedCrossRefGoogle Scholar
  54. 54.
    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(21):2129–39.PubMedCrossRefGoogle Scholar
  55. 55.
    Paez JG, Janne PA, Lee JC, Tracy S, Greulich H, Gabriel S, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004;304(5676):1497–500.PubMedCrossRefGoogle Scholar
  56. 56.
    Stephens P, Hunter C, Bignell G, Edkins S, Davies H, Teague J, et al. Lung cancer: intragenic ERBB2 kinase mutations in tumours. Nature 2004;431(7008):525–6.PubMedCrossRefGoogle Scholar
  57. 57.
    Soung YH, Lee JW, Kim SY, Wang YP, Jo KH, Moon SW, et al. Somatic mutations of the ERBB4 kinase domain in human cancers. Int J Cancer 2006;118(6):1426–9.PubMedCrossRefGoogle Scholar
  58. 58.
    Parsons DW, Wang TL, Samuels Y, Bardelli A, Cummins JM, DeLong L, et al. Colorectal cancer: mutations in a signalling pathway. Nature 2005;436(7052):792.PubMedCrossRefGoogle Scholar
  59. 59.
    Rokavec M, Justenhoven C, Schroth W, Istrate MA, Haas S, Fischer HP, et al. A novel polymorphism in the promoter region of ERBB4 is associated with breast and colorectal cancer risk. Clin Cancer Res 2007;13(24):7506–14.PubMedCrossRefGoogle Scholar
  60. 60.
    Murabito JM, Rosenberg CL, Finger D, Kreger BE, Levy D, Splansky GL, et al. A genome-wide association study of breast and prostate cancer in the NHLBI’s Framingham Heart Study. BMC Med Genet 2007;8(Suppl 1):S6.PubMedCrossRefGoogle Scholar
  61. 61.
    Suo Z, Emilsen E, Tveit KM, Nesland JM. Type 1 protein tyrosine kinases in benign and malignant breast lesions. Histopathology 1998;33(6):514–21.PubMedCrossRefGoogle Scholar
  62. 62.
    Sawyer C, Hiles I, Page M, Crompton M, Dean C. Two erbB-4 transcripts are expressed in normal breast and in most breast cancers. Oncogene 1998;17(7):919–24.PubMedCrossRefGoogle Scholar
  63. 63.
    Srinivasan R, Poulsom R, Hurst HC, Gullick WJ. Expression of the c-erbB-4/HER4 protein and mRNA in normal human fetal and adult tissues and in a survey of nine solid tumour types. J Pathol 1998;185(3):236–45.PubMedCrossRefGoogle Scholar
  64. 64.
    Srinivasan R, Gillett CE, Barnes DM, Gullick WJ. Nuclear expression of the c-erbB-4/HER-4 growth factor receptor in invasive breast cancers. Cancer Res 2000;60(6):1483–7.PubMedGoogle Scholar
  65. 65.
    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(5):758–65.PubMedCrossRefGoogle Scholar
  66. 66.
    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(11):4217–25.PubMedGoogle Scholar
  67. 67.
    Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, et al. Molecular portraits of human breast tumours. Nature 2000;406(6797):747–52.PubMedCrossRefGoogle Scholar
  68. 68.
    Knowlden JM, Gee JM, 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(15):1949–57.PubMedCrossRefGoogle Scholar
  69. 69.
    Lodge AJ, Anderson JJ, Gullick WJ, Haugk B, Leonard RC, Angus B. Type 1 growth factor receptor expression in node positive breast cancer: adverse prognostic significance of c-erbB-4. J Clin Pathol 2003;56(4):300–4.PubMedCrossRefGoogle Scholar
  70. 70.
    Bednarek AK, Laflin KJ, Daniel RL, Liao Q, Hawkins KA, Aldaz CM. WWOX, a novel WW domain-containing protein mapping to human chromosome 16q23.3-24.1, a region frequently affected in breast cancer. Cancer Res 2000;60(8):2140–5.PubMedGoogle Scholar
  71. 71.
    Bacus SS, Chin D, Yarden Y, Zelnick CR, Stern DF. Type 1 receptor tyrosine kinases are differentially phosphorylated in mammary carcinoma and differentially associated with steroid receptors. Am J Pathol 1996;148(2):549–58.PubMedGoogle Scholar
  72. 72.
    Witton CJ, Reeves JR, Going JJ, Cooke TG, Bartlett JM. Expression of the HER1-4 family of receptor tyrosine kinases in breast cancer. J Pathol 2003;200(3):290–7.PubMedCrossRefGoogle Scholar
  73. 73.
    Suo Z, Berner HS, Risberg B, Karlsson MG, Nesland JM. Estrogen receptor-alpha and C-ERBB-4 expression in breast carcinomas. Virchows Arch 2001;439(1):62–9.PubMedCrossRefGoogle Scholar
  74. 74.
    Ariazi EA, Clark GM, Mertz JE. Estrogen-related receptor alpha and estrogen-related receptor gamma associate with unfavorable and favorable biomarkers, respectively, in human breast cancer. Cancer Res 2002;62(22):6510–8.PubMedGoogle Scholar
  75. 75.
    Guler G, Iliopoulos D, Guler N, Himmetoglu C, Hayran M, Huebner K. Wwox and Ap2gamma expression levels predict tamoxifen response. Clin Cancer Res 2007;13(20):6115–21.PubMedCrossRefGoogle Scholar
  76. 76.
    Suo Z, Risberg B, Kalsson MG, Willman K, Tierens A, Skovlund E, et al. EGFR family expression in breast carcinomas. c-erbB-2 and c-erbB-4 receptors have different effects on survival. J Pathol 2002;196(1):17–25.PubMedCrossRefGoogle Scholar
  77. 77.
    Kew TY, Bell JA, Pinder SE, Denley H, Srinivasan R, Gullick WJ, et al. c-erbB-4 protein expression in human breast cancer. Br J Cancer 2000;82(6):1163–70.PubMedCrossRefGoogle Scholar
  78. 78.
    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(6):2163–8.PubMedCrossRefGoogle Scholar
  79. 79.
    Tovey SM, Witton CJ, Bartlett JM, Stanton PD, Reeves JR, Cooke TG. 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(3):R246–51.PubMedCrossRefGoogle Scholar
  80. 80.
    Abd El-Rehim DM, Pinder SE, Paish CE, Bell JA, Rampaul RS, Blamey RW, 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(8):1532–42.PubMedCrossRefGoogle Scholar
  81. 81.
    Gilbertson RJ, Perry RH, Kelly PJ, Pearson AD, Lunec J. Prognostic significance of HER2 and HER4 coexpression in childhood medulloblastoma. Cancer Res 1997;57(15):3272–80.PubMedGoogle Scholar
  82. 82.
    Tovey SM, Dunne B, Witton CJ, Cooke TG, Bartlett JM. HER4 in breast cancer: comparison of antibodies against intra- and extra-cellular domains of HER4. Breast Cancer Res 2006;8(2):R19.PubMedCrossRefGoogle Scholar
  83. 83.
    Borrell-Pages M, Rojo F, Albanell J, Baselga J, Arribas J. TACE is required for the activation of the EGFR by TGF-alpha in tumors. EMBO J 2003;22(5):1114–24.PubMedCrossRefGoogle Scholar
  84. 84.
    Elenius K, Corfas G, Paul S, Choi CJ, Rio C, Plowman GD, et al. A novel juxtamembrane domain isoform of HER4/ErbB4. Isoform-specific tissue distribution and differential processing in response to phorbol ester. J Biol Chem 1997;272(42):26761–8.PubMedCrossRefGoogle Scholar
  85. 85.
    Elenius K, Choi CJ, Paul S, Santiestevan E, Nishi E, Klagsbrun M. Characterization of a naturally occurring ErbB4 isoform that does not bind or activate phosphatidyl inositol 3-kinase. Oncogene 1999;18(16):2607–15.PubMedCrossRefGoogle Scholar
  86. 86.
    Sardi SP, Murtie J, Koirala S, Patten BA, Corfas G. Presenilin-dependent ErbB4 nuclear signaling regulates the timing of astrogenesis in the developing brain. Cell 2006;127(1):185–97.PubMedCrossRefGoogle Scholar
  87. 87.
    Sundvall M, Peri L, Maatta JA, Tvorogov D, Paatero I, Savisalo M, et al. Differential nuclear localization and kinase activity of alternative ErbB4 intracellular domains. Oncogene 2007;26(48):6905–14.PubMedCrossRefGoogle Scholar
  88. 88.
    Junttila TT, Laato M, Vahlberg T, Soderstrom KO, Visakorpi T, Isola J, et al. Identification of patients with transitional cell carcinoma of the bladder overexpressing ErbB2, ErbB3, or specific ErbB4 isoforms: real-time reverse transcription-PCR analysis in estimation of ErbB receptor status from cancer patients. Clin Cancer Res 2003;9(14):5346–57.PubMedGoogle Scholar
  89. 89.
    Gilbertson RJ, Bentley L, Hernan R, Junttila TT, Frank AJ, Haapasalo H, et al. ERBB receptor signaling promotes ependymoma cell proliferation and represents a potential novel therapeutic target for this disease. Clin Cancer Res 2002;8(10):3054–64.PubMedGoogle Scholar
  90. 90.
    Ferretti E, Di Marcotullio L, Gessi M, Mattei T, Greco A, Po A, et al. Alternative splicing of the ErbB-4 cytoplasmic domain and its regulation by hedgehog signaling identify distinct medulloblastoma subsets. Oncogene 2006;25(55):7267–73.PubMedCrossRefGoogle Scholar
  91. 91.
    Williams CC, Allison JG, Vidal GA, Burow ME, Beckman BS, Marrero L, et al. The ERBB4/HER4 receptor tyrosine kinase regulates gene expression by functioning as a STAT5A nuclear chaperone. J Cell Biol 2004;167(3):469–78.PubMedCrossRefGoogle Scholar
  92. 92.
    Komuro A, Nagai M, Navin NE, Sudol M. WW domain-containing protein YAP associates with ErbB-4 and acts as a co-transcriptional activator for the carboxyl-terminal fragment of ErbB-4 that translocates to the nucleus. J Biol Chem 2003;278(35):33334–41.PubMedCrossRefGoogle Scholar
  93. 93.
    Linggi B, Carpenter G. ErbB-4 s80 intracellular domain abrogates ETO2-dependent transcriptional repression. J Biol Chem 2006;281(35):25373–80.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Maria Sundvall
    • 1
    • 2
  • Kristiina Iljin
    • 3
  • Sami Kilpinen
    • 4
    • 5
  • Henri Sara
    • 6
  • Olli-Pekka Kallioniemi
    • 3
    • 4
    • 5
    • 6
  • Klaus Elenius
    • 1
    • 2
    • 7
    Email author
  1. 1.Department of Medical Biochemistry and Molecular BiologyUniversity of TurkuTurkuFinland
  2. 2.Medicity Research LaboratoryUniversity of TurkuTurkuFinland
  3. 3.Medical BiotechnologyVTT Technical Research CentreTurkuFinland
  4. 4.FIMM—Institute for Molecular Medicine FinlandHelsinkiFinland
  5. 5.Genome-Scale Biology Research Program, BiomedicumUniversity of HelsinkiHelsinkiFinland
  6. 6.Turku Centre for BiotechnologyUniversity of Turku and Åbo Academi UniversityTurkuFinland
  7. 7.Department of OncologyTurku University Central HospitalTurkuFinland

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