Skip to main content
SpringerLink
Log in

Expression of Ephb2 and Ephb4 in breast carcinoma

  • Article
  • Published:
Pathology & Oncology Research

Abstract

Eph receptor tyrosine kinases and their cell-surfacebound ligands, the ephrins, play key roles in diverse biological processes. Eph receptors comprise the largest family of receptor tyrosine kinases consisting of eight EphA receptors (with five corresponding ephrinA ligands) and six EphB receptors (with three corresponding transmembrane ephrinB ligands). Originally identified as neuronal pathfinding molecules, EphB receptors and ephrinB ligands are later proved to be crucial regulators of vasculogenesis and embryogenesis. More studies indicate that Eph receptors are involved in angiogenesis and tumorigenesis. This study aimed to investigate the expression of EphB2 and EphB4 in breast carcinomas. Semiquantitative RT-PCR and immunohistochemistry were used to examine the expression patterns of EphB2 and EphB4. Clinicopathological and survival correlations were statistically analyzed in a series of 94 breast carcinomas, 9 normal specimens and 4 breast carcinoma cell lines. 1(1%), 16(17%), 29(31%), 48(51%) of the 94 tumors were negative, weak, moderate and strong EphB2 protein expression, respectively. 6(6%), 27(29%), 28(30%), 33(35%) of the tumors were negative, weak, moderate and strong EphB4 expression, respectively. Both EphB2 and EphB4 RT-PCR products could be detected in all specimens. Increased EphB2 protein expression was negatively associated with overall survival, and there was a trend that increased EphB2 protein expression was correlated with shorter disease free survival, while EphB4 protein expression was associated with histological grade and stage. EphB4 membrane staining was increased with S phase fraction and associated with DNA aneuploidy. These findings indicate that both EphB2 and EphB4 are involved in the development of breast cancer and that both molecules could be potential predictive markers.

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

Access this article

Log in via an institution

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. van der Geer P, Hunter T, Lindberg RA: Receptor protein-tyrosine kinases and their signal transduction pathways. Ann Rev Cell Biol 10: 251–337, 1994.

    Article  PubMed  Google Scholar 

  2. Gale N., Holland SJ., Valenzuela DM, et al: Eph receptors and ligands comprise two major specificity subclasses and are reciprocally compartmentalized during embryogenesis. Neuron 17: 9–19, 1996.

    Article  PubMed  CAS  Google Scholar 

  3. Davy A, Gale NW, Murray EW, et al: Compartmentalized signaling by GPI-anchored ephrin-A5 requires the Fyn tyrosine kinase to regulate cellular adhesion. Genes Dev 13: 3125–3135, 1999.

    Article  PubMed  CAS  Google Scholar 

  4. Davy A., Robbins SM: Ephrin-A5 modulates cell adhesion and morphology in an integrin-dependent manner. Embo J 19: 5396–5405, 2000.

    Article  PubMed  CAS  Google Scholar 

  5. Kullander K, Klein R: Mechanisms and functions of Eph and ephrin signalling. Nat Rev Mol Cell Biol 3: 475–486, 2002.

    Article  PubMed  CAS  Google Scholar 

  6. Flanagan JG, Vanderhaeghen P: The ephrins and Eph receptors in neural development. Ann Rev Neurosci 21: 309–345, 1998.

    Article  PubMed  CAS  Google Scholar 

  7. Tessier-Lavigne M: Eph receptor tyrosine kinases, axon repulsion, and the development of topographic maps. Cell 82: 345–348, 1995.

    Article  PubMed  CAS  Google Scholar 

  8. Wang HU, Anderson DJ: Eph family transmembrane ligands can mediate repulsive guidance of trunk neural crest migration and motor axon outgrowth. Neuron 18: 383–396, 1997.

    Article  PubMed  CAS  Google Scholar 

  9. Winslow JW, Moran P, Valverde J, et al: Cloning of AL-1, alig- and for an Eph-related tyrosine kinase receptor involved in axon bundle formation. Neuron 14: 973–981, 1995.

    Article  PubMed  CAS  Google Scholar 

  10. Chinoy MR, Graybill MM, Miller SA, et al: Angiopoietin-1 and VEGF in vascular development and angiogenesis in hypoplastic lungs. Am J Physiol Lung Cell Mol Physiol 283: L60–66, 2002.

    PubMed  CAS  Google Scholar 

  11. Li H, Fredriksson L, Li X, et al: PDGF-D is a potent transforming and angiogenic growth factor. Oncogene 22: 1501–1510, 2003.

    Article  PubMed  CAS  Google Scholar 

  12. Goede V., Fleckenstein G, Dietrich M, et al: Prognostic value of angiogenesis in mammary tumors. Anticancer Res 18: 2199–2210, 1998.

    PubMed  CAS  Google Scholar 

  13. Kuehn R, Lelkes PI, Bloechle C, et al: Angiogenesis, angiogenic growth factors, and cell adhesion molecules are upregulated in chronic pancreatic diseases: angiogenesis in chronic pancreatitis and in pancreatic cancer. Pancreas 18: 96–103, 1999.

    Article  PubMed  CAS  Google Scholar 

  14. Weidner N, Folkman J, Pozza F, et al: Tumor angiogenesis: a new significant and independent prognostic indicator in earlystage breast carcinoma. J Natl Cancer Inst 84: 1875–1882, 1992.

    Article  PubMed  CAS  Google Scholar 

  15. Zelinski DP, Zantek ND, Stewart JC, et al: EphA2 overexpression causes tumorigenesis of mammary epithelial cells. Cancer Res 61: 2301–2311, 2001.

    PubMed  CAS  Google Scholar 

  16. Miyazaki T, Kato H, Fukuchi M, et al: EphA2 overexpression correlates with poor prognosis in esophageal squamous cell carcinoma. Int J Cancer 103: 657–668, 2003.

    Article  PubMed  CAS  Google Scholar 

  17. Walker-Daniels J, Coffman K, Azimi M, et al: Overexpression of the EphA2 tyrosine kinase in prostate cancer. Prostate 41: 275–281, 1999.

    Article  PubMed  CAS  Google Scholar 

  18. Ikegaki N, Tang XX, Liu XG, et al: Molecular characterization and chromosomal localization of DRT (EPHT3): a developmentally regulated human protein-tyro sine kinase gene of the EPH family. Hum Mol Genet 4: 2033–2041, 1995.

    Article  PubMed  CAS  Google Scholar 

  19. Nikolova Z, Djonov V, Zuercher G, et al: Cell-type specific and estrogen dependent expression of the receptor tyrosine kinase EphB4 and its ligand ephrin-B2 during mammary gland morphogenesis. J Cell Sci 111: 2741–2750, 1998.

    PubMed  CAS  Google Scholar 

  20. Cromer A, Carles A, Millon R, et al: Identification of genes associated with tumorigenesis and metastatic potential of hypopharyngeal cancer by microarray analysis. Oncogene (in press), 2004.

  21. Kiyokawa E, Takai S, Tanaka M, et al: Overexpression of ERK, an EPH family receptor protein tyrosine kinase, in various human tumors. Cancer Res 54: 3645–3652, 1994.

    PubMed  CAS  Google Scholar 

  22. Tang XX, Brodeur GM, Campling BG, et al: Coexpression of transcripts encoding EPHB receptor protein tyrosine kinases and their ephrin-B ligands in human small cell lung carcinoma. Clin Cancer Res 5: 455–463, 1999.

    PubMed  CAS  Google Scholar 

  23. Tang XX, Evans AE, Zhao H, et al: High-level expression of EPHB6, EFNB2, and EFNB3 is associated with low tumor stage and high TrkA expression in human neuroblastomas. Clin Cancer Res 5: 1491–1501, 1999.

    PubMed  CAS  Google Scholar 

  24. Tang XX, Evan, AE, Zhao H, et al: Association among EPHB2, TrkA, and MYCN expression in low-stage neuroblastomas. Med Pediatr Oncol 36: 80–86, 2001.

    Article  PubMed  CAS  Google Scholar 

  25. Liu W, Ahmad SA, Jung YD, et al: Coexpression of ephrin-Bs and their receptors in colon carcinoma. Cancer 94: 934–943, 2002.

    Article  PubMed  CAS  Google Scholar 

  26. Kataoka H, Tanaka M, Kanamori M, et al: Expression profile of EFNB1, EFNB2, two ligands of EPHB2 in human gastric cancer. J Cancer Res Clin Oncol 128: 343–352, 2002.

    Article  PubMed  CAS  Google Scholar 

  27. Bennett BD, Wang Z, Kuang WJ, et al: Cloning and characterization of HTK, a novel transmembrane tyrosine kinase of the EPH subfamily. J Biol Chem 269: 14211–14220, 1994.

    PubMed  CAS  Google Scholar 

  28. Bercla G, Karamitopoulou E, Mazzucchelli L, et al: Activation of the receptor protein tyrosine kinase EphB4 in endometrial hyperplasia and endometrial carcinoma. Ann Oncol 14: 220–227, 2003.

    Article  Google Scholar 

  29. Stephenson SA, Slomka S, Douglas EL, et al: Receptor protein tyrosine kinase EphB4 is up-regulated in colon cancer. BMC Mol Biol 2: 15–21, 2001.

    Article  PubMed  CAS  Google Scholar 

  30. Berclaz G, Flutsch B, Altermatt HJ, et al: Loss of EphB4 receptor tyrosine kinase protein expression during carcinogenesis of the human breast. Oncol Rep 9: 985–993, 2002.

    PubMed  CAS  Google Scholar 

  31. Elston CW, Elli, IO: Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. Histopathology 19: 403–411, 1991.

    Article  PubMed  CAS  Google Scholar 

  32. Suo Z, Berner HS, Risberg B, et al: Estrogen receptor-alpha and C-ERBB-4 expression in breast carcinomas. Virchows Arch 439: 62–73, 2001.

    Article  PubMed  CAS  Google Scholar 

  33. Himanen JP, Rajashankar KR, Lackmann M, et al: Crystal structure of an Eph receptor-ephrin complex. Nature 414: 933–939, 2001.

    Article  PubMed  CAS  Google Scholar 

  34. Kalo MS, Pasquale EB: Multiple in vivo tyrosine phosphorylation sites in EphB receptors. Biochemistry 38: 14396–14401, 1999.

    Article  PubMed  CAS  Google Scholar 

  35. Dodelet VC, Pazzagli C, Zisch AH, et al: A novel signaling intermediate, SHEP1, directly couples Eph receptors to R-Ras and Rapl A. J Biol Chem 274: 31941–31946, 1999.

    Article  PubMed  CAS  Google Scholar 

  36. Holland SJ, Gale NW, Gish GD, et al: Juxtamembrane tyrosine residues couple the Eph family receptor EphB2/Nuk to specific SH2 domain proteins in neuronal cells. Embo J 16: 3877–3884, 1997.

    Article  PubMed  CAS  Google Scholar 

  37. Ellis C, Kasmi F, Ganju P, et al: A juxtamembrane autophosphorylation site in the Eph family receptor tyrosine kinase, Sek, mediates high affinity interaction with p59fyn. Oncogene 12: 1727–1733, 1996.

    PubMed  CAS  Google Scholar 

  38. Steinte JJ, Meininger CJ, Forough R, et al: Eph B4 receptor signaling mediates endothelial cell migration and proliferation via the phosphatidylinositol 3-kinase pathway. J Biol Chem 277: 43830–43836, 2002.

    Article  CAS  Google Scholar 

  39. Vindis C, Cerretti DP, Daniel TO, et al: EphB1 recruits c-Src and p52Shc to activate MAPK/ERK and promote chemotaxis. J Cell Biol 162: 661–669, 2003.

    Article  PubMed  CAS  Google Scholar 

  40. Stein E, Cerretti DP, Daniel TO: Ligand activation of ELK receptor tyrosine kinase promotes its association with Grb10 and Grb2 in vascular endothelial cells. J Biol Chem 271: 23588–23596, 1996.

    Article  PubMed  CAS  Google Scholar 

  41. Stein E, Huynh-Do U, Lane AA, et al: Nck recruitment to Eph receptor, EphB1/ELK, couples ligand activation to c-Jun kinase. J Biol Chem 273: 1303–1312, 1998.

    Article  PubMed  CAS  Google Scholar 

  42. Hock B, Bohme B, Karn T, et al: PDZ-domain-mediated interaction of the Eph-related receptor tyrosine kinase EphB3 and the ras-binding protein AF6 depends on the kinase activity of the receptor. Proc Natl Acad Sci U S A 95: 9779–9785, 1998.

    Article  PubMed  CAS  Google Scholar 

  43. Stein E, Lane AA, Cerretti DP, et al: Eph receptors discriminate specific ligand oligomers to determine alternative signaling complexes, attachment, and assembly responses. Genes Dev 12: 667–672, 1998.

    Article  PubMed  CAS  Google Scholar 

  44. Wybenga-Groot LE, Baskin B, Ong SH, et al: Structural basis for autoinhibition of the Ephb2 receptor tyrosine kinase by the unphosphorylated juxtamembrane region. Cell 106: 745–753, 2001.

    Article  PubMed  CAS  Google Scholar 

  45. Matsuzaki M, Nagase S, Abe T, et al: Detailed deletion mapping on chromosome 1p32–p36 in human colorectal cancer: identification of three distinct regions of common allelic loss. Int J Oncol 13: 1229–1238, 1998.

    PubMed  CAS  Google Scholar 

  46. Praml C, Finke LH, Herfarth C, et al: Deletion mapping defines different regions in 1p34.2-pter that may harbor genetic information related to human colorectal cancer. Oncogene 11: 1357–1367, 1995.

    PubMed  CAS  Google Scholar 

  47. Oba SM, Wang YJ, Song JP, et al: Genomic structure and loss of heterozygosity of EPHB2 in colorectal cancer. Cancer Lett 164:97–109, 2001.

    Article  PubMed  CAS  Google Scholar 

  48. Adams RH: Vascular patterning by Eph receptor tyrosine kinases and ephrins. Semin Cell Dev Biol 13: 55–63, 2002.

    Article  PubMed  CAS  Google Scholar 

  49. Wang HU, Chen ZF, Anderson DJ: Molecular distinction and angiogenic interaction between embryonic arteries and veins revealed by ephrin-B2 and its receptor Eph-B4. Cell 93: 741–753, 1998.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pathology, The Norwegian Radium Hospital, University of Oslo, N-0310, Oslo, Norway

    Qinghua Wu, Zhenhe Suo, Bjørn Risberg & Jahn M. Nesland

  2. Department of Pathology, Örebro Medical Center Hospital, Örebro, Sweden

    Mats G. Karlsson

  3. Department of Oncology, Örebro Medical Center Hospital, Örebro, Sweden

    Kenneth Villman

Authors
  1. Qinghua Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zhenhe Suo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Bjørn Risberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mats G. Karlsson
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kenneth Villman
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jahn M. Nesland
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Zhenhe Suo.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wu, Q., Suo, Z., Risberg, B. et al. Expression of Ephb2 and Ephb4 in breast carcinoma. Pathol. Oncol. Res. 10, 26–33 (2004). https://doi.org/10.1007/BF02893405

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02893405

Keywords

Search

Navigation