Ovarian Cancer pp 247-258 | Cite as

EGF/ErbB Receptor Family in Ovarian Cancer

  • N. J. Maihle
  • A. T. Baron
  • B. A. Barrette
  • C. H. Boardman
  • T. A. Christensen
  • E. M. Cora
  • J. M. Faupel-Badger
  • T. Greenwood
  • S. C. Juneja
  • J. M. Lafky
  • H. Lee
  • J. L. Reiter
  • K. C. Podratz
Part of the Cancer Treatment and Research book series (CTAR, volume 107)


The EGF/ErbB receptor family is comprised of four members: ErbB1, ErbB2, ErbB3 and ErbB4 (Fig. 1). The human EGF receptor (i.e., EGFR/ErbB1) is the prototype in this family, and is distinguished by its ability to interact with a large number of polypeptide growth factors with high affinity (Fig. 2). The two most widely studied members of this ligand family are epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-α). Overexpression of ErbB 1 results in ligand-dependent, anchorage independent growth of primary cells in culture (1–4). Although a causative link between pertur bation of expression of human EGFR and human cancers has not yet been established, EGFR gene amplification and rearrangements have been reported in a variety of human carcinomas, including breast and ovarian cancer. The molecular biology and biochemistry of human EGFR have been studied extensively. The gene encoding this receptor has been isolated and characterized, the promoter region has been mapped, and several transcripts have been identified in normal human tissues (5–10). Furthermore, the biochemical characterization of EGFR has been pioneering in the field of polypeptide hormone receptor research. In 1980, Stanley Cohen and his colleagues demonstrated, for the first time, that the human EGFR expressed intrinsic tyrosine kinase activity (11). Numerous studies have since contributed to our current understanding of the biosynthesis, post-translational processing, and cellular trafficking of this receptor, and these studies have been reviewed (12–14).


Ovarian Cancer Epidermal Growth Factor Receptor Human Epidermal Growth Factor Receptor Epithelial Ovarian Cancer Epidermal Growth Factor Receptor Gene 
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  1. 1.
    Di Fiore, P.P., Pierce J.H., Fleming T.P., Hazan R., Ullrich A., King C.R., Schlessinger J. and Aaronson S.A. Overexpression of the human EGF receptor confers an EGFdependent transformed phenotype to NIH 3T3 cells. Cell 1987; 51: 1063–1070.PubMedCrossRefGoogle Scholar
  2. 2.
    Lax, I., Johnson A., Howk R., Sap J., Bellot F., Winkler M., Ullrich A., Vennstrom B., Schlessinger J. and Givol D. Chicken epidermal growth factor (EGF) receptor: cDNA cloning, expression in mouse cells, and differential binding of EGF and transforming growth factor alpha. Mol. Cell. Biol. 1988; 8: 1970–1978.PubMedGoogle Scholar
  3. 3.
    Riedel, H., Massoglia S., Schlessinger J. and Ullrich A. Ligand activation of overexpressed epidermal growth factor receptors transforms NIH 3T3 mouse fibroblasts. Proc. Natl. Acad. Sci. 1988; 85: 1477–1481.PubMedCrossRefGoogle Scholar
  4. 4.
    Velu, T.J., Beguinot L., Vass W.C., Willingham M.C., Merlino G.T., Pastan I. and Lowy D.R. Epidermal growth factor-dependent transformation by a human EGF receptor proto-oncogene. Science 1987; 238: 1408–1410.PubMedCrossRefGoogle Scholar
  5. 5.
    Ullrich, A., Coussens L., Hayflick J.S., Dull T.J., Gray A., Tam A.W., Lee J., Yarden Y., Libermann T.A., Schlessinger J., Downward J., Mayes E.L.V., Whittle N., Waterfield M.D. and Seeburg P.H. Human epidermal growth factor receptor cDNA sequence and aberrant expression of the amplified gene in A431 epidermoid carcinoma cells. Nature 1984; 309: 418–425.PubMedCrossRefGoogle Scholar
  6. 6.
    Lin, C.R., Chen W.S., Kruiger W., Stolarsky L.S., Weber W., Evans R.M., Verma I.M., Gill G.N. and Rosenfeld M.G. Expression cloning of human EGF receptor complementary DNA: gene amplification and three related messenger RNA products in A431 cells. Science 1984; 224: 843–848.PubMedCrossRefGoogle Scholar
  7. 7.
    Ishii, S., Xu Y.-h., Stratton R.H., Roe B.A., Merlino G.T. and Pastan I. Characterization and sequence of the promoter region of the human epidermal growth factor receptor gene. Proc. Natl. Acad. Sci. 1985; 82: 4920–4924.PubMedCrossRefGoogle Scholar
  8. 8.
    Haley, J., Whittle N., Bennett P., Kinchington D., Ullrich A. and Waterfield M. The human EGF receptor gene: structure of the 110 kb locus and identification of sequences regulating its transcription. Oncogene Res. 1987; 1: 375–396.PubMedGoogle Scholar
  9. 9.
    Reiter, J.L. and Maihle N.J. A 1.8 kb alternative transcript from the human epidermal growth factor receptor gene encodes a truncated form of the receptor. Nucl. Acids Res. 1996; 24: 4050–4056.PubMedCrossRefGoogle Scholar
  10. 10.
    Reiter, J.L., Threadgill D.W., Eley G.D., Strunk K.E., Danielsen A.J., Schehl Sinclair C., Pearsall R.S., Green P.J., Yee D., Lampland A.L., Balasubramaniam S., Crossley T.D., Magnuson T.R., James C.D. and Maihle N.J. Comparative genomic sequence analysis and isolation of human and mouse alternative EGFR transcripts encoding truncated receptor isoforms. Genomics 2001; In Press.Google Scholar
  11. 11.
    Cohen, S., Carpenter G. and King L., Jr. Epidermal growth factor-receptor-protein kinase interactions. Co-purification of receptor and epidermal growth factor-enhanced phosphorylation activity. J. Biol. Chem. 1980; 255: 4834–4842.PubMedGoogle Scholar
  12. 12.
    Carpenter, G. and Cohen S. Epidermal growth factor. J. Biol. Chem. 1990; 265: 77097712.Google Scholar
  13. 13.
    Carpenter, G. and Wahl M.I. The epidermal growth factor family. In Sporn, M.B. and Roberts, A.B. (eds), Peptide Growth Factors and Their Receptors. Springer-Verlag, New York, pp. 69–171, 1990.CrossRefGoogle Scholar
  14. 14.
    Prigent, S.A. and Lemoine N.R. The type I (EGFR-related) family of growth factor receptors and their ligands. Prog. Growth Factor Res. 1992; 4: 1–24.PubMedCrossRefGoogle Scholar
  15. 15.
    Klapper, L.N., Glathie S., Vaisman N., Hynes N.E., Andrews G.C., Sela M. and Yarden Y. The ErbB-2/HER2 oncoprotein of human carcinomas may function solely as a shared coreceptor for multiple stroma-derived growth factors. Proc. Nati. Acad. Sci. USA 1999; 96: 4995–5000.CrossRefGoogle Scholar
  16. 16.
    Scott, G.K., Robles R., Park J.W., Montgomery P.A., Daniel J., Holmes W.E., Lee J., Keller G.A., Li W.-L., Fendly B.M., Wood W.I., Shepard H.M. and Benz C.C. A truncated intracellular HER2/neu receptor produced by alternative RNA processing affects growth of human carcinoma cells. Mol. Cell. Biol. 1993; 13: 2247–2257.PubMedGoogle Scholar
  17. 17.
    Doherty, J.K., Bond C., Jardim A., Adelman J.P. and Clinton G.M. The HER-2/neu receptor tyrosine kinase gene encodes a secreted autoinhibitor. Proc. Natl. Acad. Sci. USA 1999; 96: 10869–10874.PubMedCrossRefGoogle Scholar
  18. 18.
    Katoh, M., Yazaki Y., Sugimura T. and Terada M. c-erbB3 gene encodes secreted as well as transmembrane receptor tyrosine kinase. Biochem. Biophys. Res. Commun. 1993; 192: 1189–1197.Google Scholar
  19. 19.
    Lee, H. and Maihle N.J. 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.PubMedCrossRefGoogle Scholar
  20. 20.
    Yarden, Y. and Schlessinger J. Epidermal growth factor induces rapid, reversible aggregation of the purified epidermal growth factor receptor. Biochem. 1997; 26: 1443 1551.Google Scholar
  21. 21.
    Spaargaren, M., Defize L.H.K., Boonstra J. and de Laat S.W. Antibody-induced dimerization activates the epidermal growth factor receptor tyrosine kinase. J. Biol. Chem. 1991; 266: 1733–1739.PubMedGoogle Scholar
  22. 22.
    Spivak-Kroizman, T., Rotin D., Pinchasi D., Ullrich A., Schlessinger J. and Lax I. Heterodimerization of c-erbB2 with different epidermal growth factor receptor mutants elicits stimulatory or inhibitory responses. J. Biol. Chem. 1992; 267: 8056–8063.Google Scholar
  23. 23.
    Zhou, M., Felder S., Rubinstein M., Hurwitz D.R., Ullrich A., Lax I. and Schlessinger J. Real-time measurements of kinetics of EGF binding to soluble EGF receptor monomers and dimers support the dimerization model for receptor activation. Biochem. 1993; 32: 8193–8198.CrossRefGoogle Scholar
  24. 24.
    Biswas, R., Basu M., Sen-Majumdar A. and Das M. Intrapeptide autophosphorylation of the epidermal growth factor receptor: regulation of kinase catalytic function by receptor dimerization. Biochem. 1985; 24: 3795–3802.CrossRefGoogle Scholar
  25. 25.
    Koland, J.G. and Cerione R.A. Growth factor control of epidermal growth factor receptor kinase activity via an intramolecular mechanism. J. Biol. Chem. 1988; 263: 2230–2237.Google Scholar
  26. 26.
    Northwood, I.C. and Davis R.J. Activation of the epidermal growth factor receptor tyrosine protein kinase in the absence of receptor oligomerization. J. Biol. Chem. 1988; 263: 7450–7453.Google Scholar
  27. 27.
    Carraway, K.L., III and Cerione R.A. Inhibition of epidermal growth factor receptor aggregation by an antibody directed against the epidermal growth factor receptor extracellular domain. J. Biol. Chem. 1993; 268: 23860–23867.Google Scholar
  28. 28.
    Boerner, J.L., Danielsen A.J., McManus M.J. and Maihle N.J. Activation of Rho is required for ligand-independent oncogenic signaling by a mutant EGF receptor. J. Biol. Chem.2000; In Press.Google Scholar
  29. 29.
    McManus, M.J., Boerner J.L., Danielsen A.J., Wang Z., Matsumura F. and Maihle N.J. An oncogenic epidermal growth factor receptor signals via a p21-activated kinasecaldesmon-myosin phosphotyrosine complex. J. Biol. Chem. 2000; 275: 35328–35334.Google Scholar
  30. 30.
    Hung, M.-C. and Lau Y.-K. Basic science of HER-2/neu: A review. Semin. Oncol. 1999; 26 (Suppl 12): 51–59.PubMedGoogle Scholar
  31. 31.
    Riese, D.J., II and Stern D.F. Specificity within the EGF family/ErbB receptor family signaling network. BioEssays 1998; 20: 41–48.PubMedCrossRefGoogle Scholar
  32. 32.
    Olayioye, M.A., Neve R.M., Lane H.A. and Hynes N.E. The ErbB signaling network: receptor heterodimerization in development and cancer. EMBO J. 2000; 19: 31593167.Google Scholar
  33. 33.
    Petch, L.A., Harris J., Raymond V.W., Blasband A., Lee D.C. and Earp H.S. A truncated, secreted form of the epidermal growth factor receptor is encoded by an alternatively spliced transcript in normal rat tissue. Mol. Cell. Bio1. 1990; 10: 2973 2982.Google Scholar
  34. 34.
    Maihle, N.J., Flickinger T.W., Raines M.A., Sanders M.L. and Kung H.-J. Native avian c-erbB gene expresses a secreted protein product corresponding to the ligand-binding domain of the receptor. Proc. Natl. Acad. Sci. 1991; 88: 1825–1829.CrossRefGoogle Scholar
  35. 35.
    Flickinger, T.W., Maihle N.J. and Kung H.-J. An alternatively processed mRNA from the avian c-erbB gene encodes a soluble, truncated form of the receptor that can block ligand-dependent transformation. Mol. Cell. Biol. 1992; 12: 883–893.Google Scholar
  36. 36.
    Johnson, D.E., Lee P.L., Lu J. and Williams L.T. Diverse forms of a receptor for acidic and basic fibroblast growth factors. Mol. Cell. Biol. 1990; 10: 4728–4736.PubMedGoogle Scholar
  37. 37.
    Downing, J.R., Roussel M.F. and Sherr C.J. Ligand and protein kinase C downmodulate the colony-stimulating factor 1 receptor by independent mechanisms. Mol. Cell. Biol. 1989; 9: 2890–2896.PubMedGoogle Scholar
  38. 38.
    Baumbach, W.R., Homer D.L. and Logan J.S. The growth hormone-binding protein in rat serum is an alternatively spliced form of the rat growth hormone receptor. Genes Dev 1989; 3: 1199–1205.PubMedCrossRefGoogle Scholar
  39. 39.
    DiStefano, P.S. and Johnson E.M., Jr. Identification of a truncated form of the nerve growth factor receptor. Proc. Natl. Acad. Sci. 1988; 85: 270–274.PubMedCrossRefGoogle Scholar
  40. 40.
    Schall, T.J., Lewis M., Koller K.J., Lee A., Rice G.C., Wong G.H.W., Gatanaga T., Granger G.A., Lentz R., Raab H., Kohr W.J. and Goeddel D.V. Molecular cloning and expression of a receptor for human tumor necrosis factor. Celi 1990; 61: 361–370.CrossRefGoogle Scholar
  41. 41.
    Loosfelt, H., Misrahi M., Atger M., Salesse R., Vu Hai-Luu Thi M.T., Jolivet A., Guiochon-Mantel A., Sar S., Jallal B., Gamier J. and Milgrom E. Cloning and sequencing of porcine LH-hCG receptor cDNA: variants lacking transmembrane domain. Science 1989; 245: 525–528.Google Scholar
  42. 42.
    Rubin, L.A., Kurman C.C., Fritz M.E., Biddison W.E., Boutin B., Yarchoan R. and Nelson D.L. Soluble interleukin 2 receptors are released from activated human lymphoid cells in vitro. J. Immunol. 1985; 135: 3172–3177.PubMedGoogle Scholar
  43. 43.
    Mosley, B., Beckmann M.P., March C.J., Idzerda R.L., Gimpel S.D., VandenBos T., Friend D., Alpert A., Anderson D., Jackson J., Wignall J.M., Smith C., Gallis B., Sims J.E., Urdal D., Widmar M.B., Cosman D. and Park L.S. The murine interleukin-4 receptor: molecular cloning and characterization of secreted and membrane bound forms. Cell 1989; 59: 335–348.PubMedCrossRefGoogle Scholar
  44. 44.
    Lust, J.A., Donovan K.A., Kline M.P., Greipp P.R., Kyle R.A. and Maihle N.J. Isolation of an mRNA encoding a soluble form of the human interleukin-6 receptor. Cytokine 1992; 4: 96–100.PubMedCrossRefGoogle Scholar
  45. 45.
    Goodwin, R.G., Friend D., Ziegler S.F., Jerzy R., Falk B.A., Gimpel S., Cosman D., Dower S.K., March C.J., Namen A.E. and Park L.S. Cloning of the human and murine interleukin-7 receptors: demonstration of a soluble form and homology to a new receptor superfamily. Cell 1990; 60: 941–951.PubMedCrossRefGoogle Scholar
  46. 46.
    Merlino, G.T., Ishii S., Whang-Peng J., Knutsen T., Xu Y.-H., Clark A.J.L., Stratton R.H., Wilson R.K., Ma D.P., Roe B.A., Hunts J.H., Shimizu N. and Pastan I. Structure and localization of genes encoding aberrant and normal epidermal growth factor receptor RNAs from A431 human carcinoma cells. Mol. Cell. Biol. 1985; 5: 1722 1734.Google Scholar
  47. 47.
    Garcia, J.V., Gehm B.D. and Rosner M.R. An evolutionarily conserved enzyme degrades transforming growth factor-alpha as well as insulin. J. Cell. Biol. 1989; 109: 1301–1307.PubMedCrossRefGoogle Scholar
  48. 48.
    Basu, A., Raghunath M., Bishayee S. and Das M. Inhibition of tyrosine kinase activity of the epidermal growth factor (EGF) receptor by a truncated receptor form that binds to EGF: role for interreceptor interaction in kinase regulation. Mol. Cell. Biol. 1989; 9: 671–677.PubMedGoogle Scholar
  49. 49.
    Ilekis, J.V., Gariti J., Niederberger C. and Scoccia B. Expression of a truncated epidermal growth factor receptor-like protein (TEGFR) in ovarian cancer. Gynecologic Oncol. 1997; 65: 36–41.CrossRefGoogle Scholar
  50. 50.
    Fanslow, W.C., Sims J.E., Sassenfeld H., Morrissey P.J., Gillis S., Dower S.K. and Widmer M.B. Regulation of alloreactivity in vivo by a soluble form of the interleukin1 receptor. Science 1990; 248: 739–742.PubMedCrossRefGoogle Scholar
  51. 51.
    Weisman, H.F., Bartow T., Leppo M.K., Marsh H.C., Jr., Carson G.R., Concino M.F., Boyle M.P., Roux K.H., Weisfeldt M.L. and Fearon D.T. Soluble human complement receptor type 1: in vivo inhibitor of complement suppressing post-ischemic myocardial inflammation and necrosis. Science 1990; 249: 146–151.PubMedCrossRefGoogle Scholar
  52. 52.
    Berger, E.A., Fuerst T.R. and Moss B. A soluble recombinant polypeptide comprising the amino-terminal half of the extracellular region of the CD4 molecule contains an active binding site for human immunodeficiency virus. Proc. Nati. Acad. Sci.I998; 85: 2357–2361.Google Scholar
  53. 53.
    Fisher, R.A., Bertonis J.M., Meier W., Johnson V.A., Costopoulos D.S., Liu T., Tizard R., Walker B.D., Hirsch M.S. and Schooley R.T. HIV infection is blocked in vitro by recombinant soluble CD4. Nature 1988; 331: 76–8.Google Scholar
  54. 54.
    Nemerow, G.R., Mullen J.J., III, Dickson P.W. and Cooper N.R. Soluble recombinant CR2 (CD21) inhibits Epstein-Barr virus infection. J. Viro1. 1990; 64: 1348–1352.Google Scholar
  55. 55.
    Marlin, S.D., Staunton D.E., Springer T.A., Stratowa C., Sommergruber W. and Merluzzi V.J. A soluble form of intercellular adhesion molecular-1 inhibits rhinovirus infection. Nature 1990; 344: 70–72.PubMedCrossRefGoogle Scholar
  56. 56.
    Doraiswamy, V., Parrott J.A. and Skinner M.K. Expression and action of transforming growth factor alpha in normal ovarian surface epithelium and ovarian cancer. Biol. Reprod. 2000; 63: 789–796.PubMedCrossRefGoogle Scholar
  57. 57.
    Berchuck, A., Rodriguez G.C., Kamel A., Dodge R.K., Soper J.T., Clarke-Pearson D.L. and Bast Jr. R.C. Epidermal growth factor receptor expression in normal ovarian epithelium and ovarian cancer. I. Correlation of receptor expression with prognostic factors in patients with ovarian cancer. Am. J Obstet. Gynecol. 1991; 164: 669–674.PubMedGoogle Scholar
  58. 58.
    Gullick, W.J. Prevalence of aberrant expression of the epidermal growth factor receptor in human cancers. Br. Med. Bull. 1991; 47: 87–98.Google Scholar
  59. 59.
    Salomon, D.S., Brandt R., Ciardiello F. and Normanno N. Epidermal growth factor-related peptides and their receptors in human malignancies. Crit. Rev. Oncol./Hematol. 1995; 19: 183–232.CrossRefGoogle Scholar
  60. 60.
    Baron, A.T., Lafky J.M., Connolly D.C., Peoples J.J., O’Kane D.J., Suman V.J., Boardman C.H., Podratz K.C. and Maihle N.J. A sandwich type acridinium-linked immunosorbent assay (ALISA) detects soluble ErbB1 (sErbBl) in normal human sera. J. Immunol. Methods 1998; 219: 23–43.Google Scholar
  61. 61.
    Baron, A.T., Lafky J.M., Boardman C.H., Balasubramaniam S., Suman V.J., Podratz K.C. and Maihle N.J. Serum sErbBl and epidermal growth factor levels as tumor biomarkers in women with stage III or IV epithelial ovarian cancer. Cancer Epidemiol. Biomarkers Prey., 1999; 8: 129–137.Google Scholar
  62. 62.
    Yazici, H., Dolapcioglu K., Buyru F. and Dalay N. Utility of c-erbB-2 expression in tissue and sera of ovarian cancer patients. Cancer Invest. 2000; 18: 110–114.PubMedCrossRefGoogle Scholar
  63. 63.
    Slamon, D.J., Godolphin W., Jones L.A., Holt J.A., Wong S.G., Keith D.E., Levin W.J., Stuart S.G., Udove J., Ullrich A. and Press M.F. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 1989; 244: 707–712.PubMedCrossRefGoogle Scholar
  64. 64.
    Wu, J.T., Astill M.E. and Zhang P. Detection of the extracellular domain of c-erbB-2 oncoprotein in sera from patients with various carcinomas: correlation with tumor markers. J. Clin. Lab. Anal. 1993; 7: 31–40.PubMedCrossRefGoogle Scholar
  65. 65.
    McKenzie, S.J., DeSombre K.A., Bast B.S., Hollis D.R., Whitaker R.S., Berchuck A., Boyer C.M. and Bast R.C., Jr. Serum levels of HER-2 neu (c-erbB-2) correlate with overexpression of p185neu in human ovarian cancer. Cancer 1993; 71: 3942–3946.PubMedCrossRefGoogle Scholar
  66. 66.
    Molina, R., Jo J., Filella X., Bruix J., Castells A., Hague M. and Ballesta A.M. Serum levels of c-erbB-2 (HER-2/neu) in patients with malignant and non-malignant diseases. Tumor Biol. 1997; 18: 188–196.CrossRefGoogle Scholar
  67. 67.
    Cheung, T.H., Wong Y.F., Chung T.K., Maimonis P. and Chang A.M. Clinical use of serum c-erbB-2 in patients with ovarian masses. Gynecol. Obstet. Invest. 1999; 48: 133–137.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2002

Authors and Affiliations

  • N. J. Maihle
    • 1
  • A. T. Baron
    • 1
  • B. A. Barrette
    • 2
  • C. H. Boardman
    • 2
  • T. A. Christensen
    • 1
  • E. M. Cora
    • 3
  • J. M. Faupel-Badger
    • 1
  • T. Greenwood
    • 1
  • S. C. Juneja
    • 1
  • J. M. Lafky
    • 1
  • H. Lee
    • 1
  • J. L. Reiter
    • 1
  • K. C. Podratz
    • 2
  1. 1.Tumor Biology ProgramUSA
  2. 2.Department of Obstetrics/GynecologyMayo ClinicRochesterUSA
  3. 3.Department of Biochemistry & Nutrition, Medical Sciences Campus, School of MedicineUniversity of Puerto RicoSan JuanUSA

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