Skip to main content
NCBI home page
British Journal of Cancer logoLink to British Journal of Cancer
. 2000 Feb 21;82(6):1163–1170. doi: 10.1054/bjoc.1999.1057

c-erbB-4 protein expression in human breast cancer

T Y Kew 1, J A Bell 1, S E Pinder 1, H Denley 1, R Srinivasan 2, W J Gullick 2, R I Nicholson 3, R W Blamey 1, I O Ellis 1
PMCID: PMC2363344  PMID: 10735500

Abstract

The Type 1 family of growth factor receptors includes epidermal growth factor receptor (EGFR), c- erb B-2, c- erb B-3 and c- erb B-4. Overexpression of the first two members is associated with poorer prognosis in patients with breast carcinoma. In this study we examined the expression of c- erb B-4 protein using the monoclonal antibody HFR-1. A total of 127 consecutive cases of primary operable invasive breast carcinoma presenting between 1975 and 1977 were studied. All patients were managed by simple mastectomy or conservation surgery with radiotherapy and no adjuvant therapy given. Long-term follow-up was maintained. Routine, formalin-fixed, paraffin-embedded tumour samples were used and sections were stained immunohistochemically using the Duet StreptABC method. Immunoreactivity was classified using a simple semi-quantitative scoring method. Protein expression was generally low but definite positive cytoplasmic, membranous and nuclear reactivity was identified in 58%, 41% and 25% of cases respectively. Expression at all three sites demonstrated significant inverse associations were histological grade. In addition, membrane accentuation correlated inversely with the Nottingham Prognostic Index (NPI), while cytoplasmic reactivity showed a positive association with c- erb B-3 expression. No significant associations were found with disease-free interval or survival. The results of this study demonstrate that higher levels of c- erb B-4 protein expression are associated with a more differentiated histological phenotype in contrast to the other members of the Type 1 family. Larger series with extended follow-up will be required to ascertain definitively the prognostic value of c- erb B-4 expression in breast carcinoma. © 2000 Cancer Research Campaign

Keywords: breast cancer, c-erbB-4, growth factor receptor, prognostic factors

Full Text

The Full Text of this article is available as a PDF (196.8 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bacus S. S., Chin D., Yarden Y., Zelnick C. R., Stern D. F. Type 1 receptor tyrosine kinases are differentially phosphorylated in mammary carcinoma and differentially associated with steroid receptors. Am J Pathol. 1996 Feb;148(2):549–558. [PMC free article] [PubMed] [Google Scholar]
  2. Baulida J., Kraus M. H., Alimandi M., Di Fiore P. P., Carpenter G. All ErbB receptors other than the epidermal growth factor receptor are endocytosis impaired. J Biol Chem. 1996 Mar 1;271(9):5251–5257. doi: 10.1074/jbc.271.9.5251. [DOI] [PubMed] [Google Scholar]
  3. Busfield S. J., Michnick D. A., Chickering T. W., Revett T. L., Ma J., Woolf E. A., Comrack C. A., Dussault B. J., Woolf J., Goodearl A. D. Characterization of a neuregulin-related gene, Don-1, that is highly expressed in restricted regions of the cerebellum and hippocampus. Mol Cell Biol. 1997 Jul;17(7):4007–4014. doi: 10.1128/mcb.17.7.4007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Carpenter G. Receptors for epidermal growth factor and other polypeptide mitogens. Annu Rev Biochem. 1987;56:881–914. doi: 10.1146/annurev.bi.56.070187.004313. [DOI] [PubMed] [Google Scholar]
  5. Carraway K. L., 3rd, Weber J. L., Unger M. J., Ledesma J., Yu N., Gassmann M., Lai C. Neuregulin-2, a new ligand of ErbB3/ErbB4-receptor tyrosine kinases. Nature. 1997 May 29;387(6632):512–516. doi: 10.1038/387512a0. [DOI] [PubMed] [Google Scholar]
  6. Chang C. P., Lazar C. S., Walsh B. J., Komuro M., Collawn J. F., Kuhn L. A., Tainer J. A., Trowbridge I. S., Farquhar M. G., Rosenfeld M. G. Ligand-induced internalization of the epidermal growth factor receptor is mediated by multiple endocytic codes analogous to the tyrosine motif found in constitutively internalized receptors. J Biol Chem. 1993 Sep 15;268(26):19312–19320. [PubMed] [Google Scholar]
  7. Chang H., Riese D. J., 2nd, Gilbert W., Stern D. F., McMahan U. J. Ligands for ErbB-family receptors encoded by a neuregulin-like gene. Nature. 1997 May 29;387(6632):509–512. doi: 10.1038/387509a0. [DOI] [PubMed] [Google Scholar]
  8. Earp H. S., Dawson T. L., Li X., Yu H. Heterodimerization and functional interaction between EGF receptor family members: a new signaling paradigm with implications for breast cancer research. Breast Cancer Res Treat. 1995 Jul;35(1):115–132. doi: 10.1007/BF00694752. [DOI] [PubMed] [Google Scholar]
  9. Elenius K., Corfas G., Paul S., Choi C. J., Rio C., Plowman G. D., Klagsbrun M. A novel juxtamembrane domain isoform of HER4/ErbB4. Isoform-specific tissue distribution and differential processing in response to phorbol ester. J Biol Chem. 1997 Oct 17;272(42):26761–26768. doi: 10.1074/jbc.272.42.26761. [DOI] [PubMed] [Google Scholar]
  10. 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 Mar 17;16(6):1268–1278. doi: 10.1093/emboj/16.6.1268. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Ellis I. O., Galea M., Broughton N., Locker A., Blamey R. W., Elston C. W. Pathological prognostic factors in breast cancer. II. Histological type. Relationship with survival in a large study with long-term follow-up. Histopathology. 1992 Jun;20(6):479–489. doi: 10.1111/j.1365-2559.1992.tb01032.x. [DOI] [PubMed] [Google Scholar]
  12. Elston C. W., Ellis I. O. 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. 1991 Nov;19(5):403–410. doi: 10.1111/j.1365-2559.1991.tb00229.x. [DOI] [PubMed] [Google Scholar]
  13. 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. 1995 Nov 23;378(6555):390–394. doi: 10.1038/378390a0. [DOI] [PubMed] [Google Scholar]
  14. Gilbertson R. J., Perry R. H., Kelly P. J., Pearson A. D., Lunec J. Prognostic significance of HER2 and HER4 coexpression in childhood medulloblastoma. Cancer Res. 1997 Aug 1;57(15):3272–3280. [PubMed] [Google Scholar]
  15. Haugen D. R., Akslen L. A., Varhaug J. E., Lillehaug J. R. Expression of c-erbB-3 and c-erbB-4 proteins in papillary thyroid carcinomas. Cancer Res. 1996 Mar 15;56(6):1184–1188. [PubMed] [Google Scholar]
  16. Haybittle J. L., Blamey R. W., Elston C. W., Johnson J., Doyle P. J., Campbell F. C., Nicholson R. I., Griffiths K. A prognostic index in primary breast cancer. Br J Cancer. 1982 Mar;45(3):361–366. doi: 10.1038/bjc.1982.62. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Higashiyama S., Horikawa M., Yamada K., Ichino N., Nakano N., Nakagawa T., Miyagawa J., Matsushita N., Nagatsu T., Taniguchi N. A novel brain-derived member of the epidermal growth factor family that interacts with ErbB3 and ErbB4. J Biochem. 1997 Sep;122(3):675–680. doi: 10.1093/oxfordjournals.jbchem.a021806. [DOI] [PubMed] [Google Scholar]
  18. Hollywood D. P., Hurst H. C. A novel transcription factor, OB2-1, is required for overexpression of the proto-oncogene c-erbB-2 in mammary tumour lines. EMBO J. 1993 Jun;12(6):2369–2375. doi: 10.1002/j.1460-2075.1993.tb05891.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Holmes W. E., Sliwkowski M. X., Akita R. W., Henzel W. J., Lee J., Park J. W., Yansura D., Abadi N., Raab H., Lewis G. D. Identification of heregulin, a specific activator of p185erbB2. Science. 1992 May 22;256(5060):1205–1210. doi: 10.1126/science.256.5060.1205. [DOI] [PubMed] [Google Scholar]
  20. Kageyama R., Merlino G. T., Pastan I. Epidermal growth factor (EGF) receptor gene transcription. Requirement for Sp1 and an EGF receptor-specific factor. J Biol Chem. 1988 May 5;263(13):6329–6336. [PubMed] [Google Scholar]
  21. Klijn J. G., Berns P. M., Schmitz P. I., Foekens J. A. The clinical significance of epidermal growth factor receptor (EGF-R) in human breast cancer: a review on 5232 patients. Endocr Rev. 1992 Feb;13(1):3–17. doi: 10.1210/edrv-13-1-3. [DOI] [PubMed] [Google Scholar]
  22. Knowlden J. M., Gee J. M., Seery L. T., Farrow L., Gullick W. J., Ellis I. O., Blamey R. W., Robertson J. F., Nicholson R. I. c-erbB3 and c-erbB4 expression is a feature of the endocrine responsive phenotype in clinical breast cancer. Oncogene. 1998 Oct 15;17(15):1949–1957. doi: 10.1038/sj.onc.1202107. [DOI] [PubMed] [Google Scholar]
  23. 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 Dec 4;15(23):2841–2848. doi: 10.1038/sj.onc.1201458. [DOI] [PubMed] [Google Scholar]
  24. Lemoine N. R., Barnes D. M., Hollywood D. P., Hughes C. M., Smith P., Dublin E., Prigent S. A., Gullick W. J., Hurst H. C. Expression of the ERBB3 gene product in breast cancer. Br J Cancer. 1992 Dec;66(6):1116–1121. doi: 10.1038/bjc.1992.420. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Lewis G. D., Lofgren J. A., McMurtrey A. E., Nuijens A., Fendly B. M., Bauer K. D., Sliwkowski M. X. Growth regulation of human breast and ovarian tumor cells by heregulin: Evidence for the requirement of ErbB2 as a critical component in mediating heregulin responsiveness. Cancer Res. 1996 Mar 15;56(6):1457–1465. [PubMed] [Google Scholar]
  26. Lewis S., Locker A., Todd J. H., Bell J. A., Nicholson R., Elston C. W., Blamey R. W., Ellis I. O. Expression of epidermal growth factor receptor in breast carcinoma. J Clin Pathol. 1990 May;43(5):385–389. doi: 10.1136/jcp.43.5.385. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Li W., Park J. W., Nuijens A., Sliwkowski M. X., Keller G. A. Heregulin is rapidly translocated to the nucleus and its transport is correlated with c-myc induction in breast cancer cells. Oncogene. 1996 Jun 6;12(11):2473–2477. [PubMed] [Google Scholar]
  28. Lovekin C., Ellis I. O., Locker A., Robertson J. F., Bell J., Nicholson R., Gullick W. J., Elston C. W., Blamey R. W. c-erbB-2 oncoprotein expression in primary and advanced breast cancer. Br J Cancer. 1991 Mar;63(3):439–443. doi: 10.1038/bjc.1991.101. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Lyne J. C., Melhem M. F., Finley G. G., Wen D., Liu N., Deng D. H., Salup R. Tissue expression of neu differentiation factor/heregulin and its receptor complex in prostate cancer and its biologic effects on prostate cancer cells in vitro. Cancer J Sci Am. 1997 Jan-Feb;3(1):21–30. [PubMed] [Google Scholar]
  30. Pereira H., Pinder S. E., Sibbering D. M., Galea M. H., Elston C. W., Blamey R. W., Robertson J. F., Ellis I. O. Pathological prognostic factors in breast cancer. IV: Should you be a typer or a grader? A comparative study of two histological prognostic features in operable breast carcinoma. Histopathology. 1995 Sep;27(3):219–226. doi: 10.1111/j.1365-2559.1995.tb00213.x. [DOI] [PubMed] [Google Scholar]
  31. Pinder S. E., Ellis I. O., Galea M., O'Rouke S., Blamey R. W., Elston C. W. Pathological prognostic factors in breast cancer. III. Vascular invasion: relationship with recurrence and survival in a large study with long-term follow-up. Histopathology. 1994 Jan;24(1):41–47. doi: 10.1111/j.1365-2559.1994.tb01269.x. [DOI] [PubMed] [Google Scholar]
  32. Plowman G. D., Culouscou J. M., Whitney G. S., Green J. M., Carlton G. W., Foy L., Neubauer M. G., Shoyab M. Ligand-specific activation of HER4/p180erbB4, a fourth member of the epidermal growth factor receptor family. Proc Natl Acad Sci U S A. 1993 Mar 1;90(5):1746–1750. doi: 10.1073/pnas.90.5.1746. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Plowman G. D., Green J. M., Culouscou J. M., Carlton G. W., Rothwell V. M., Buckley S. Heregulin induces tyrosine phosphorylation of HER4/p180erbB4. Nature. 1993 Dec 2;366(6454):473–475. doi: 10.1038/366473a0. [DOI] [PubMed] [Google Scholar]
  34. Riese D. J., 2nd, Bermingham Y., van Raaij T. M., Buckley S., Plowman G. D., Stern D. F. 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 Jan 18;12(2):345–353. [PubMed] [Google Scholar]
  35. Slamon D. J., Clark G. M., Wong S. G., Levin W. J., Ullrich A., McGuire W. L. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987 Jan 9;235(4785):177–182. doi: 10.1126/science.3798106. [DOI] [PubMed] [Google Scholar]
  36. Srinivasan R., Poulsom R., Hurst H. C., Gullick W. J. 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 Jul;185(3):236–245. doi: 10.1002/(SICI)1096-9896(199807)185:3<236::AID-PATH118>3.0.CO;2-7. [DOI] [PubMed] [Google Scholar]
  37. Todd J. H., Dowle C., Williams M. R., Elston C. W., Ellis I. O., Hinton C. P., Blamey R. W., Haybittle J. L. Confirmation of a prognostic index in primary breast cancer. Br J Cancer. 1987 Oct;56(4):489–492. doi: 10.1038/bjc.1987.230. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Travis A., Pinder S. E., Robertson J. F., Bell J. A., Wencyk P., Gullick W. J., Nicholson R. I., Poller D. N., Blamey R. W., Elston C. W. C-erbB-3 in human breast carcinoma: expression and relation to prognosis and established prognostic indicators. Br J Cancer. 1996 Jul;74(2):229–233. doi: 10.1038/bjc.1996.342. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Vecchi M., Baulida J., Carpenter G. Selective cleavage of the heregulin receptor ErbB-4 by protein kinase C activation. J Biol Chem. 1996 Aug 2;271(31):18989–18995. doi: 10.1074/jbc.271.31.18989. [DOI] [PubMed] [Google Scholar]
  40. Vecchi M., Carpenter G. Constitutive proteolysis of the ErbB-4 receptor tyrosine kinase by a unique, sequential mechanism. J Cell Biol. 1997 Nov 17;139(4):995–1003. doi: 10.1083/jcb.139.4.995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Wen D., Suggs S. V., Karunagaran D., Liu N., Cupples R. L., Luo Y., Janssen A. M., Ben-Baruch N., Trollinger D. B., Jacobsen V. L. Structural and functional aspects of the multiplicity of Neu differentiation factors. Mol Cell Biol. 1994 Mar;14(3):1909–1919. doi: 10.1128/mcb.14.3.1909. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Zhang D., Sliwkowski M. X., Mark M., Frantz G., Akita R., Sun Y., Hillan K., Crowley C., Brush J., Godowski P. J. Neuregulin-3 (NRG3): a novel neural tissue-enriched protein that binds and activates ErbB4. Proc Natl Acad Sci U S A. 1997 Sep 2;94(18):9562–9567. doi: 10.1073/pnas.94.18.9562. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Zhu X., Lai C., Thomas S., Burden S. J. Neuregulin receptors, erbB3 and erbB4, are localized at neuromuscular synapses. EMBO J. 1995 Dec 1;14(23):5842–5848. doi: 10.1002/j.1460-2075.1995.tb00272.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Zimonjic D. B., Alimandi M., Miki T., Popescu N. C., Kraus M. H. Localization of the human HER4/erbB-4 gene to chromosome 2. Oncogene. 1995 Mar 16;10(6):1235–1237. [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES