Skip to main content
PMC home page
British Journal of Cancer logoLink to British Journal of Cancer
. 1995 Jul;72(1):56–64. doi: 10.1038/bjc.1995.277

Expression and activation of erbB-2 and epidermal growth factor receptor in lung adenocarcinomas.

W J Rachwal 1, P F Bongiorno 1, M B Orringer 1, R I Whyte 1, S P Ethier 1, D G Beer 1
PMCID: PMC2034126  PMID: 7599067

Abstract

ErbB-2 and EGFR (epidermal growth factor receptor) are expressed in lung adenocarcinomas and associated with a poor prognosis. Immunocytochemical analysis revealed erbB-2 and EGFR coexperession as a characteristic feature of most lung adenocarcinomas, and at levels of receptor expression present in bronchial epithelial cells. In primary lung tumours and cell lines, erbB-2 detected using Western blot analysis demonstrated low-level phosphotyrosine staining of the 185 kDa band, as compared with breast cancer cell lines. A549 and A427 lung adenocarcinoma cells treated with neu differentiation factor (NDF) showed increased erbB-2 phosphotyrosine staining, but to a much lesser extent than breast cancer cells. The lung cells were examined for expression of the potential autocrine growth factors NDF and transforming growth factor alpha (TGF-alpha) by Northern blot analysis. Both NDF and TFG-alpha mRNA were abundantly expressed in the A549 cells. NDF mRNA was highest during active cell proliferation and decreased in confluent cells or after treatment with the growth-inhibitory steroid dexamethasone. Primary tumours and cell lines expressed EGFR, showing higher basal level phosphotyrosine staining than erbB-2. Treatment with NDF and EGF (epidermal growth factor) stimulated cell growth, and in A549 cells the presence of both factors provided an additive increase in cell growth. The growth stimulus that ligand-activated erbB-2 and EGFR provides to lung adenocarcinoma cells may establish a background of continued cell proliferation over which other critical transforming events may occur.

Full text

PDF
56

Images in this article

58Figure 1
on p.58
59Figure 2
on p.59
60Figure 3
on p.60
61Figure 4
on p.61
62Figure 5
on p.62

Selected References

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

  1. Bongiorno P. F., Whyte R. I., Lesser E. J., Moore J. H., Orringer M. B., Beer D. G. Alterations of K-ras, p53, and erbB-2/neu in human lung adenocarcinomas. J Thorac Cardiovasc Surg. 1994 Feb;107(2):590–595. [PubMed] [Google Scholar]
  2. Chazin V. R., Kaleko M., Miller A. D., Slamon D. J. Transformation mediated by the human HER-2 gene independent of the epidermal growth factor receptor. Oncogene. 1992 Sep;7(9):1859–1866. [PubMed] [Google Scholar]
  3. Connelly P. A., Stern D. F. The epidermal growth factor receptor and the product of the neu protooncogene are members of a receptor tyrosine phosphorylation cascade. Proc Natl Acad Sci U S A. 1990 Aug;87(16):6054–6057. doi: 10.1073/pnas.87.16.6054. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Croxtall J. D., Waheed S., Choudhury Q., Anand R., Flower R. J. N-terminal peptide fragments of lipocortin-1 inhibit A549 cell growth and block EGF-induced stimulation of proliferation. Int J Cancer. 1993 Apr 22;54(1):153–158. doi: 10.1002/ijc.2910540124. [DOI] [PubMed] [Google Scholar]
  5. Dazzi H., Hasleton P. S., Thatcher N., Barnes D. M., Wilkes S., Swindell R., Lawson R. A. Expression of epidermal growth factor receptor (EGF-R) in non-small cell lung cancer. Use of archival tissue and correlation of EGF-R with histology, tumour size, node status and survival. Br J Cancer. 1989 May;59(5):746–749. doi: 10.1038/bjc.1989.156. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Derynck R., Roberts A. B., Winkler M. E., Chen E. Y., Goeddel D. V. Human transforming growth factor-alpha: precursor structure and expression in E. coli. Cell. 1984 Aug;38(1):287–297. doi: 10.1016/0092-8674(84)90550-6. [DOI] [PubMed] [Google Scholar]
  7. Di Fiore P. P., Pierce J. H., Kraus M. H., Segatto O., King C. R., Aaronson S. A. erbB-2 is a potent oncogene when overexpressed in NIH/3T3 cells. Science. 1987 Jul 10;237(4811):178–182. doi: 10.1126/science.2885917. [DOI] [PubMed] [Google Scholar]
  8. Di Marco E., Pierce J. H., Fleming T. P., Kraus M. H., Molloy C. J., Aaronson S. A., Di Fiore P. P. Autocrine interaction between TGF alpha and the EGF-receptor: quantitative requirements for induction of the malignant phenotype. Oncogene. 1989 Jul;4(7):831–838. [PubMed] [Google Scholar]
  9. Dittadi R., Gion M., Pagan V., Brazzale A., Del Maschio O., Bargossi A., Busetto A., Bruscagnin G. Epidermal growth factor receptor in lung malignancies. Comparison between cancer and normal tissue. Br J Cancer. 1991 Oct;64(4):741–744. doi: 10.1038/bjc.1991.390. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Ethier S. P., Mahacek M. L., Gullick W. J., Frank T. S., Weber B. L. Differential isolation of normal luminal mammary epithelial cells and breast cancer cells from primary and metastatic sites using selective media. Cancer Res. 1993 Feb 1;53(3):627–635. [PubMed] [Google Scholar]
  11. Hanson L. A., Nuzum E. O., Jones B. C., Malkinson A. M., Beer D. G. Expression of the glucocorticoid receptor and K-ras genes in urethan-induced mouse lung tumors and transformed cell lines. Exp Lung Res. 1991 Mar-Apr;17(2):371–387. doi: 10.3109/01902149109064425. [DOI] [PubMed] [Google Scholar]
  12. 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]
  13. Kern J. A., Schwartz D. A., Nordberg J. E., Weiner D. B., Greene M. I., Torney L., Robinson R. A. p185neu expression in human lung adenocarcinomas predicts shortened survival. Cancer Res. 1990 Aug 15;50(16):5184–5187. [PubMed] [Google Scholar]
  14. Kokai Y., Dobashi K., Weiner D. B., Myers J. N., Nowell P. C., Greene M. I. Phosphorylation process induced by epidermal growth factor alters the oncogenic and cellular neu (NGL) gene products. Proc Natl Acad Sci U S A. 1988 Aug;85(15):5389–5393. doi: 10.1073/pnas.85.15.5389. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Lehman T. A., Bennett W. P., Metcalf R. A., Welsh J. A., Ecker J., Modali R. V., Ullrich S., Romano J. W., Appella E., Testa J. R. p53 mutations, ras mutations, and p53-heat shock 70 protein complexes in human lung carcinoma cell lines. Cancer Res. 1991 Aug 1;51(15):4090–4096. [PubMed] [Google Scholar]
  16. Noguchi M., Murakami M., Bennett W., Lupu R., Hui F., Jr, Harris C. C., Gerwin B. I. Biological consequences of overexpression of a transfected c-erbB-2 gene in immortalized human bronchial epithelial cells. Cancer Res. 1993 May 1;53(9):2035–2043. [PubMed] [Google Scholar]
  17. Osaki A., Toi M., Yamada H., Kawami H., Kuroi K., Toge T. Prognostic significance of co-expression of c-erbB-2 oncoprotein and epidermal growth factor receptor in breast cancer patients. Am J Surg. 1992 Oct;164(4):323–326. doi: 10.1016/s0002-9610(05)80897-9. [DOI] [PubMed] [Google Scholar]
  19. Pavelic K., Banjac Z., Pavelic J., Spaventi S. Evidence for a role of EGF receptor in the progression of human lung carcinoma. Anticancer Res. 1993 Jul-Aug;13(4):1133–1137. [PubMed] [Google Scholar]
  20. Peles E., Ben-Levy R., Tzahar E., Liu N., Wen D., Yarden Y. Cell-type specific interaction of Neu differentiation factor (NDF/heregulin) with Neu/HER-2 suggests complex ligand-receptor relationships. EMBO J. 1993 Mar;12(3):961–971. doi: 10.1002/j.1460-2075.1993.tb05737.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. 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]
  22. Press M. F., Cordon-Cardo C., Slamon D. J. Expression of the HER-2/neu proto-oncogene in normal human adult and fetal tissues. Oncogene. 1990 Jul;5(7):953–962. [PubMed] [Google Scholar]
  23. Press M. F., Hung G., Godolphin W., Slamon D. J. Sensitivity of HER-2/neu antibodies in archival tissue samples: potential source of error in immunohistochemical studies of oncogene expression. Cancer Res. 1994 May 15;54(10):2771–2777. [PubMed] [Google Scholar]
  24. Rusch V., Baselga J., Cordon-Cardo C., Orazem J., Zaman M., Hoda S., McIntosh J., Kurie J., Dmitrovsky E. Differential expression of the epidermal growth factor receptor and its ligands in primary non-small cell lung cancers and adjacent benign lung. Cancer Res. 1993 May 15;53(10 Suppl):2379–2385. [PubMed] [Google Scholar]
  25. Segatto O., Lonardo F., Pierce J. H., Bottaro D. P., Di Fiore P. P. The role of autophosphorylation in modulation of erbB-2 transforming function. New Biol. 1990 Feb;2(2):187–195. [PubMed] [Google Scholar]
  26. Shin D. M., Ro J. Y., Hong W. K., Hittelman W. N. Dysregulation of epidermal growth factor receptor expression in premalignant lesions during head and neck tumorigenesis. Cancer Res. 1994 Jun 15;54(12):3153–3159. [PubMed] [Google Scholar]
  27. 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]
  28. 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. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science. 1989 May 12;244(4905):707–712. doi: 10.1126/science.2470152. [DOI] [PubMed] [Google Scholar]
  29. Sozzi G., Miozzo M., Tagliabue E., Calderone C., Lombardi L., Pilotti S., Pastorino U., Pierotti M. A., Della Porta G. Cytogenetic abnormalities and overexpression of receptors for growth factors in normal bronchial epithelium and tumor samples of lung cancer patients. Cancer Res. 1991 Jan 1;51(1):400–404. [PubMed] [Google Scholar]
  30. Speirs V., Ray K. P., Freshney R. I. Paracrine control of differentiation in the alveolar carcinoma, A549, by human foetal lung fibroblasts. Br J Cancer. 1991 Oct;64(4):693–699. doi: 10.1038/bjc.1991.383. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Stöcklin E., Botteri F., Groner B. An activated allele of the c-erbB-2 oncogene impairs kidney and lung function and causes early death of transgenic mice. J Cell Biol. 1993 Jul;122(1):199–208. doi: 10.1083/jcb.122.1.199. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Suda Y., Aizawa S., Furuta Y., Yagi T., Ikawa Y., Saitoh K., Yamada Y., Toyoshima K., Yamamoto T. Induction of a variety of tumors by c-erbB2 and clonal nature of lymphomas even with the mutated gene (Val659----Glu659). EMBO J. 1990 Jan;9(1):181–190. doi: 10.1002/j.1460-2075.1990.tb08094.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Tateishi M., Ishida T., Mitsudomi T., Kaneko S., Sugimachi K. Immunohistochemical evidence of autocrine growth factors in adenocarcinoma of the human lung. Cancer Res. 1990 Nov 1;50(21):7077–7080. [PubMed] [Google Scholar]
  34. Veale D., Kerr N., Gibson G. J., Kelly P. J., Harris A. L. The relationship of quantitative epidermal growth factor receptor expression in non-small cell lung cancer to long term survival. Br J Cancer. 1993 Jul;68(1):162–165. doi: 10.1038/bjc.1993.306. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Velu T. J., Beguinot L., Vass W. C., Willingham M. C., Merlino G. T., Pastan I., Lowy D. R. Epidermal-growth-factor-dependent transformation by a human EGF receptor proto-oncogene. Science. 1987 Dec 4;238(4832):1408–1410. doi: 10.1126/science.3500513. [DOI] [PubMed] [Google Scholar]
  36. Wada T., Qian X. L., Greene M. I. Intermolecular association of the p185neu protein and EGF receptor modulates EGF receptor function. Cell. 1990 Jun 29;61(7):1339–1347. doi: 10.1016/0092-8674(90)90697-d. [DOI] [PubMed] [Google Scholar]
  37. Weiner D. B., Nordberg J., Robinson R., Nowell P. C., Gazdar A., Greene M. I., Williams W. V., Cohen J. A., Kern J. A. Expression of the neu gene-encoded protein (P185neu) in human non-small cell carcinomas of the lung. Cancer Res. 1990 Jan 15;50(2):421–425. [PubMed] [Google Scholar]
  38. Xu Y. H., Ishii S., Clark A. J., Sullivan M., Wilson R. K., Ma D. P., Roe B. A., Merlino G. T., Pastan I. Human epidermal growth factor receptor cDNA is homologous to a variety of RNAs overproduced in A431 carcinoma cells. 1984 Jun 28-Jul 4Nature. 309(5971):806–810. doi: 10.1038/309806a0. [DOI] [PubMed] [Google Scholar]
  39. Yu D., Wang S. S., Dulski K. M., Tsai C. M., Nicolson G. L., Hung M. C. c-erbB-2/neu overexpression enhances metastatic potential of human lung cancer cells by induction of metastasis-associated properties. Cancer Res. 1994 Jun 15;54(12):3260–3266. [PubMed] [Google Scholar]

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

RESOURCES