Skip to main content
Log in

The type 1 growth factor receptor family: new ligands and receptors and their role in breast cancer

  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

The type 1 family of growth factor receptors, which consist of the epidermal growth factor receptor, c-erbB-2, c-erbB-3, and c-erbB-4, are expressed in normal breast ductal epithelial cells and in some breast cancers. Nine genes have now been identified which code for ligands. In some cases the genes are spliced into a series of proteins which differ in structure, but all retain an EGF-like element responsible for receptor recognition.

The EGF receptor is expressed in normal breast and in some cancers, but is apparently reduced in expression in other cases. Cancers with EGF receptors appear to represent a greater threat to patients as in most studies they are associated with a shorter time to relapse and overall survival. The c-erbB-2 protein is overexpressed at very high levels in about one fifth of breast cancers and is indicative of poor prognosis. Other cancers may express lesser degrees of overexpression but it is not clear if this is biologically or clinically significant. The c-erbB-3 protein is expressed in normal breast epithelial cells and has been reported to be present at high levels in some cancers but at normal levels or at lower than normal levels in some others. The limited studies to date suggest that when measured on its own c-erbB-3 expression is not predictive. c-erbB-4 is also expressed in normal breast and in some cancers but no studies have yet been performed to address whether it is associated with disease behaviour.

In the future it is likely that a greater understanding of the function of this complex family of interacting proteins will assist in gaining the maximum predictive power from measurement of their expression in human breast cancer.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Cohen S: EGF and its receptor: historical perspective. J Mam Gland Biol Neoplasia 2:93-96, 1997

    Google Scholar 

  2. Riese DJ, van Raaij TM, Plowman GD, Andrews GC, Stern DF: The cellular response to neuregulins is governed by complex interactions of the erbB receptor family. Mol Cell Biol 15:5770-5776, 1995

    Google Scholar 

  3. Tzahar E, Waterman H, Chen X, Levkowitz G, Karunagaran D, Lavi S, Ratzkin BJ, Yarden Y: A hierarchical network of interreceptor interactions determines signal transduction by neu differentiation factor/neuregulin and epidermal growth factor. Mol Cell Biol 16:5276-5287, 1996

    Google Scholar 

  4. Riese DJ, 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-β. Oncogene 12:345-353, 1996

    Google Scholar 

  5. 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 Journal 16:1268-1278, 1997

    Google Scholar 

  6. 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 15:2841-2848, 1997

    Google Scholar 

  7. Tzahar E, Levkowitz G, Karunagaran D, Yi L, Peles E, Lavi S, Chang D, Liu N, Yayon A, Wen D, Yarden Y: ErbB-3 and ErbB-4 function as the respective low and high affinity receptors of all neu differentiation factor/heregulin isoforms. J Biol Chem 269:25226-25233, 1994

    Google Scholar 

  8. Beerli RR, Hynes NE: Epidermal growth factor-related peptides activate distinct subsets of ErbB receptors and differ in their biological activities. J Biol Chem 271:6071-6076, 1996

    Google Scholar 

  9. Chang H, Riese DJ, Gilbert W, Stern DF, McMahan UJ: Ligands for ErbB-family receptors encoded by a neuregulin-like gene. Nature 387:509-512, 1997

    Google Scholar 

  10. Carraway KL, Weber JL, Unger MJ, Ledesma J, Yu N, Gassmann M, Lai C: Neuregulin-2, a new ligand of ErbB3/ErbB4-receptor tyrosine kinases. Nature 387:512-516, 1997

    Google Scholar 

  11. Busfield SJ, Michnick DA, Chickering TW, Revett TL, Ma J, Woolf EA, Comrack CA, Dussault BJ, Woolf J, Goodearl ADJ, Gearing DP: Characterization of a neuregulin-related gene, Don-1, that is highly expressed in restricted regions of the cerebellum and hippocampus. Mol Cell Biol 17:4007-4014, 1997

    Google Scholar 

  12. Zhang D, Sliwkowski MX, Mark M, Frantz G, Akita R, Sun Y, Hillan K, Crowley C, Brush J, Godowski PJ: Neuregulin-3 (NRG3): a novel neural tissue-enriched protein that binds and activates ErbB4. Proc Natl Acad Sci USA 94:9562-9567, 1997

    Google Scholar 

  13. Alimandi M, Wang LM, Bottaro D, Lee CC, Kuo A, Frankel M, Fedi P, Tang C, Lippman M, Pierce JH: Epidermal growth factor and betacellulin mediate signal transduction through co-expressed ErbB2 and ErB3 receptors. EMBO J 16:5608-5617, 1997

    Google Scholar 

  14. Barbacci EG, Guarino BC, Stroh JG, Singleton DH, Rosnack KJ, Moyer JD, Andrews GC: The structural basis for the specificity of EGF and heregulin binding. J Biol Chem 270:9585-9589, 1995

    Google Scholar 

  15. Gullick WJ: A new model for the interaction of EGF-like ligands with their receptors: the new one-two. Eur J Cancer 30A:2186, 1994

    Google Scholar 

  16. Tzahar E, Pinkas-Kramarski R, Moyer JD, Kapper LN, Alroy I, Levkowitz G, Shelly M, Henis S, Eisenstein M, Ratzkin BJ, Sela M, Andrews GC, Yarden Y: Bivalence of EGF-like ligands drives the erbB signaling network. EMBO J 16:4938-4950, 1997

    Google Scholar 

  17. Guilliford TJ, Huang GC, Ouyang XM, Epstein RJ: Reduced ability of transforming growth-factor-alpha to induce EGF receptor heterodimerization and down-regulation suggests a mechanism of oncogenic synergy with erbb2. Oncogene 18:2219-2223, 1997

    Google Scholar 

  18. Pinkas-Kramarski R, Alroy I, Yarden Y: ErbB receptors and EGF-like ligands: cell lineage determination and oncogenesis through combinatorial signaling. J Mam Gland Biol Neoplasia 2:97-107, 1997

    Google Scholar 

  19. Pinkas-Kramarski R, Shelly M, Glathe S, Ratzkin BJ, Yarden Y: Neu differentiation factor/neuregulin isoforms activate distinct receptor combinations. J Biol Chem 271:19029-19032, 1996

    Google Scholar 

  20. Schweitzer R, Howes R, Smith R, Shilo B-Z, Freeman M: Inhibition of Drosophila EGF receptor activation by the secreted protein argos. Nature 376:699-702, 1995

    Google Scholar 

  21. Sandrock AW, Dryer SE, Rosen KM, Gozani SN, Kramer R, Theill LE, Fischback GD: Maintenance of acetylcholine receptor number by neuregulins at the neuromuscular junction in vivo. Science 276:599-603, 1997

    Google Scholar 

  22. Clarke RB, Howell A, Potten CS, Anderson E: Dissociation between steroid receptor expression and cell proliferation in the human breast. Cancer Res 57:4987-4991, 1997

    Google Scholar 

  23. Hendler FJ, Ozanne BW: Human squamous cell lung cancers express increased epidermal growth factor receptors. J Clin Invest 74:647-651, 1984

    Google Scholar 

  24. Sainsbury JRC, Farndon JR, Needham GK, Malcolm AJ, Harris AL: Epidermal growth factor receptor status as predictor of early recurrence of and death from breast cancer. Lancet 1:1398-1402, 1987

    Google Scholar 

  25. Robertson KW, Reeves JR, Smith G, Keith WN, Ozanne BW, Cooke TG, Stanton PD: Quantitative estimation of epidermal growth factor receptor and c-erbB-2 in human breast cancer. Cancer Res 56:3823-3830, 1996

    Google Scholar 

  26. 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 235:177-182, 1987

    Google Scholar 

  27. Gullick WJ: The c-erbB3/HER3 receptor in human cancer. Cancer Surveys 27:339-349, 1996

    Google Scholar 

  28. Prigent SA, Lemoine NR, Hughes CM, Plowman GD, Selden C, Gullick WJ: Expression of the c-erbB-3 protein in normal human adult and fetal tissues. Oncogene 7:1273-1278, 1992

    Google Scholar 

  29. 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 389:725-730, 1997

    Google Scholar 

  30. 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 17:1642-1659, 1997

    Google Scholar 

  31. Marchionni MA, Kirk CJ, Isaacs IJ, Hoban CJ, Mahanthappa NK, Anton ES, Chen C, Wason F, Lawson D, Hamers FPT, Canoll PD, Reynolds R, Cannella B, Meun D, Holt WF, Matthew WD, Chen LE, Gispen WH, Raine CS, Salzer JL, Gwynne DI: Neuregulins as potential drugs for neurological disorders. Cold Spring Harbor Symp Quant Biol 61:459-472, 1996

    Google Scholar 

  32. Bobrow LG, Millis RR, Happerfield LC, Gullick WJ: c-erbB-3 protein expression in ductal carcinoma in situ of the breast. Eur J Cancer 33:1846-1850, 1997

    Google Scholar 

  33. Travis A, Pinder SE, Robertson JFR, Bell JA, Wencyk P, Gullick WJ, Nicholson RI, Poller DN, Blamey RW, Elston CW, Ellis IO: c-erbB-3 in human breast carcinoma: expression and relation to prognosis and established prognostic indicators. Br J Cancer 74:229-233, 1996

    Google Scholar 

  34. Elenius K, Corfas G, Paul S, Choi CJ, Rio C, Plowman GD, Klagsbrun M: A novel juxtamembrane domain isoform of HER4/ErbB4. J Biol Chem 272:26761-26768, 1997

    Google Scholar 

  35. Arribas J, Lopez-Casillas F, Massague J: Role of the juxtamembrane domains of the transforming growth factor-α precursor and the β-amyloid precursor protein in regulated ectodomain shedding. J Biol Chem 272:17160-17165, 1997

    Google Scholar 

  36. Vecchi M, Baulida J, Carpenter G: Selective cleavage of the heregulin receptor ErbB-4 by protein kinase C activation. J Biol Chem 271:18989-18995, 1996

    Google Scholar 

  37. Vecchi M, Carpenter G: Constitutive proteolysis of the ErbB-4 receptor tyrosine kinase by a unique, sequential mechanism. J Cell Biol 139:995-1003, 1997

    Google Scholar 

  38. Cohen BD, Green JM, Foy L, Fell PH: HER4-mediated biological and biochemical properties in NIH 3T3 cells. J Biol Chem 271:4813-4818, 1996

    Google Scholar 

  39. 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 271:5251-5257, 1996

    Google Scholar 

  40. Pinkas-Kramarski R, Eilam R, Alroy I, Levkowitz G, Lonai P, Yarden Y: Differential expression of NDF/neuregulin receptors ErbB-3 and ErbB-4 and involvement in inhibition of neuronal differentiation. Oncogene 15:2803-2815, 1997

    Google Scholar 

  41. Gassmann M, Casagranda F, Orioli D, Simon H, Lai C, Klein R, Lemke G: Aberrant neural and cardiac development in mice lacking the ErbB4 neuregulin receptor. Nature 378:390-394, 1995

    Google Scholar 

  42. Srinivasan R, Poulsom R, Hurst HC, Gullick WJ: Expression of the c-erbB4/HER4 protein and mRNA in normal human foetal and adult tissues and in a sample survey of nine solid tumour types. J Pathol 185:236-245, 1998

    Google Scholar 

  43. Li W, Park JW, Nuijens A, Sliwkowski MX, Keller GA: Heregulin is rapidly translocated to the nucleus and its transport is correlated with c-myc induction in breast cancer cells. Oncogene 12:2473-2477, 1996

    Google Scholar 

  44. 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 148:549-558, 1996

    Google Scholar 

  45. Plowman GD, Culouscou JM, Whitney GS, Green JM, Carlton GW, Fox L, Neubauer G, Shoyab M: Ligand-specfic activation of HER4/p180erbB4, a fourth member of the epidermal growth factor receptor family. Proc Natl Acad Sci USA 90:1746-1750, 1993

    Google Scholar 

  46. Bray D, Lay S: Computer simulated evolution of a network of cell signaling molecules. Biophys J 66:972-977

Download references

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gullick, W.J., Srinivasan, R. The type 1 growth factor receptor family: new ligands and receptors and their role in breast cancer. Breast Cancer Res Treat 52, 43–53 (1998). https://doi.org/10.1023/A:1006107016969

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1006107016969

Navigation