Skip to main content
NCBI home page
British Journal of Cancer logoLink to British Journal of Cancer
. 1996 Nov;74(9):1427–1433. doi: 10.1038/bjc.1996.560

Laminin activates the p185HER2 oncoprotein and mediates growth inhibition of breast carcinoma cells.

E Tagliabue 1, E Ardini 1, R Pellegrini 1, M Campiglio 1, R Bufalino 1, M Jeschke 1, B Groner 1, M I Colnaghi 1, S Ménard 1
PMCID: PMC2074760  PMID: 8912540

Abstract

The interaction between laminin and the oncoprotein encoded by the c-erbB-2 oncogene was studied in vitro and in vivo in human breast carcinomas. In vitro analysis of breast carcinoma cell lines overexpressing p185HER2 revealed that laminin, but not fibronectin, induced tyrosine phosphorylation and down-modulation of oncoprotein membrane expression. Laminin also specifically inhibited growth of p185HER2-positive cell lines. No direct binding between the recombinant extracellular domain of p185HER2 and laminin was found. Induction of oncoprotein down-modulation by anti-integrin antibodies and coprecipitation of the oncoprotein with the beta 4 integrin subunit indicate that the interaction between p185HER2 and laminin occurs through integrin molecules. The relevance of this in vitro observation was verified in vivo by analysing the prognostic value of p185HER2 overexpression as a function of laminin production on archival paraffin-embedded sections of 887 primary breast tumours. The results revealed an association between p185HER2 overexpression and unfavourable prognosis in tumours negative for laminin production, whereas in laminin-producing tumours, the oncoprotein overexpression was not associated with tumour aggressiveness.

Full text

PDF
1427

Images in this article

1429Figure 3
on p.1429
1430Figure 6
on p.1430
1430Figure 7
on p.1430

Selected References

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

  1. Akiyama T., Sudo C., Ogawara H., Toyoshima K., Yamamoto T. The product of the human c-erbB-2 gene: a 185-kilodalton glycoprotein with tyrosine kinase activity. Science. 1986 Jun 27;232(4758):1644–1646. doi: 10.1126/science.3012781. [DOI] [PubMed] [Google Scholar]
  2. Aronheim A., Engelberg D., Li N., al-Alawi N., Schlessinger J., Karin M. Membrane targeting of the nucleotide exchange factor Sos is sufficient for activating the Ras signaling pathway. Cell. 1994 Sep 23;78(6):949–961. doi: 10.1016/0092-8674(94)90271-2. [DOI] [PubMed] [Google Scholar]
  3. Bacus S. S., Stancovski I., Huberman E., Chin D., Hurwitz E., Mills G. B., Ullrich A., Sela M., Yarden Y. Tumor-inhibitory monoclonal antibodies to the HER-2/Neu receptor induce differentiation of human breast cancer cells. Cancer Res. 1992 May 1;52(9):2580–2589. [PubMed] [Google Scholar]
  4. Ben-Levy R., Paterson H. F., Marshall C. J., Yarden Y. A single autophosphorylation site confers oncogenicity to the Neu/ErbB-2 receptor and enables coupling to the MAP kinase pathway. EMBO J. 1994 Jul 15;13(14):3302–3311. doi: 10.1002/j.1460-2075.1994.tb06632.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Berchuck A., Kamel A., Whitaker R., Kerns B., Olt G., Kinney R., Soper J. T., Dodge R., Clarke-Pearson D. L., Marks P. Overexpression of HER-2/neu is associated with poor survival in advanced epithelial ovarian cancer. Cancer Res. 1990 Jul 1;50(13):4087–4091. [PubMed] [Google Scholar]
  6. Campiglio M., Tagliabue E., Srinivas U., Pellegrini R., Martignone S., Ménard S., Colnaghi M. I., Lombardi L., Marchisio P. C. Colocalization of the p185HER2 oncoprotein and integrin alpha 6 beta 4 in Calu-3 lung carcinoma cells. J Cell Biochem. 1994 Aug;55(4):409–418. doi: 10.1002/jcb.240550402. [DOI] [PubMed] [Google Scholar]
  7. Carraway K. L., 3rd, Sliwkowski M. X., Akita R., Platko J. V., Guy P. M., Nuijens A., Diamonti A. J., Vandlen R. L., Cantley L. C., Cerione R. A. The erbB3 gene product is a receptor for heregulin. J Biol Chem. 1994 May 13;269(19):14303–14306. [PubMed] [Google Scholar]
  8. Centis F., Tagliabue E., Uppugunduri S., Pellegrini R., Martignone S., Mastroianni A., Ménard S., Colnaghi M. I. p185 HER2/neu epitope mapping with murine monoclonal antibodies. Hybridoma. 1992 Jun;11(3):267–276. doi: 10.1089/hyb.1992.11.267. [DOI] [PubMed] [Google Scholar]
  9. 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]
  10. Coussens L., Yang-Feng T. L., Liao Y. C., Chen E., Gray A., McGrath J., Seeburg P. H., Libermann T. A., Schlessinger J., Francke U. Tyrosine kinase receptor with extensive homology to EGF receptor shares chromosomal location with neu oncogene. Science. 1985 Dec 6;230(4730):1132–1139. doi: 10.1126/science.2999974. [DOI] [PubMed] [Google Scholar]
  11. 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]
  12. Dobashi K., Davis J. G., Mikami Y., Freeman J. K., Hamuro J., Greene M. I. Characterization of a neu/c-erbB-2 protein-specific activating factor. Proc Natl Acad Sci U S A. 1991 Oct 1;88(19):8582–8586. doi: 10.1073/pnas.88.19.8582. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Gullick W. J. The role of the epidermal growth factor receptor and the c-erbB-2 protein in breast cancer. Int J Cancer Suppl. 1990;5:55–61. doi: 10.1002/ijc.2910460708. [DOI] [PubMed] [Google Scholar]
  14. 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]
  15. Huang S. S., Huang J. S. Purification and characterization of the neu/erb B2 ligand-growth factor from bovine kidney. J Biol Chem. 1992 Jun 5;267(16):11508–11512. [PubMed] [Google Scholar]
  16. Hudziak R. M., Lewis G. D., Winget M., Fendly B. M., Shepard H. M., Ullrich A. p185HER2 monoclonal antibody has antiproliferative effects in vitro and sensitizes human breast tumor cells to tumor necrosis factor. Mol Cell Biol. 1989 Mar;9(3):1165–1172. doi: 10.1128/mcb.9.3.1165. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Hurwitz E., Stancovski I., Sela M., Yarden Y. Suppression and promotion of tumor growth by monoclonal antibodies to ErbB-2 differentially correlate with cellular uptake. Proc Natl Acad Sci U S A. 1995 Apr 11;92(8):3353–3357. doi: 10.1073/pnas.92.8.3353. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. 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]
  19. King C. R., Borrello I., Bellot F., Comoglio P., Schlessinger J. Egf binding to its receptor triggers a rapid tyrosine phosphorylation of the erbB-2 protein in the mammary tumor cell line SK-BR-3. EMBO J. 1988 Jun;7(6):1647–1651. doi: 10.1002/j.1460-2075.1988.tb02991.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Kita Y. A., Barff J., Luo Y., Wen D., Brankow D., Hu S., Liu N., Prigent S. A., Gullick W. J., Nicolson M. NDF/heregulin stimulates the phosphorylation of Her3/erbB3. FEBS Lett. 1994 Jul 25;349(1):139–143. doi: 10.1016/0014-5793(94)00644-x. [DOI] [PubMed] [Google Scholar]
  21. Kornberg L. J., Earp H. S., Turner C. E., Prockop C., Juliano R. L. Signal transduction by integrins: increased protein tyrosine phosphorylation caused by clustering of beta 1 integrins. Proc Natl Acad Sci U S A. 1991 Oct 1;88(19):8392–8396. doi: 10.1073/pnas.88.19.8392. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Kraus M. H., Fedi P., Starks V., Muraro R., Aaronson S. A. Demonstration of ligand-dependent signaling by the erbB-3 tyrosine kinase and its constitutive activation in human breast tumor cells. Proc Natl Acad Sci U S A. 1993 Apr 1;90(7):2900–2904. doi: 10.1073/pnas.90.7.2900. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Lee E. C., Lotz M. M., Steele G. D., Jr, Mercurio A. M. The integrin alpha 6 beta 4 is a laminin receptor. J Cell Biol. 1992 May;117(3):671–678. doi: 10.1083/jcb.117.3.671. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Luckow V. A., Summers M. D. High level expression of nonfused foreign genes with Autographa californica nuclear polyhedrosis virus expression vectors. Virology. 1989 May;170(1):31–39. doi: 10.1016/0042-6822(89)90348-6. [DOI] [PubMed] [Google Scholar]
  25. Lupu R., Colomer R., Zugmaier G., Sarup J., Shepard M., Slamon D., Lippman M. E. Direct interaction of a ligand for the erbB2 oncogene product with the EGF receptor and p185erbB2. Science. 1990 Sep 28;249(4976):1552–1555. doi: 10.1126/science.2218496. [DOI] [PubMed] [Google Scholar]
  26. Martignone S., Pellegrini R., Villa E., Tandon N. N., Mastroianni A., Tagliabue E., Ménard S., Colnaghi M. I. Characterization of two monoclonal antibodies directed against the 67 kDa high affinity laminin receptor and application for the study of breast carcinoma progression. Clin Exp Metastasis. 1992 Nov;10(6):379–386. doi: 10.1007/BF00133466. [DOI] [PubMed] [Google Scholar]
  27. Matsuda S., Kadowaki Y., Ichino M., Akiyama T., Toyoshima K., Yamamoto T. 17 beta-estradiol mimics ligand activity of the c-erbB2 protooncogene product. Proc Natl Acad Sci U S A. 1993 Nov 15;90(22):10803–10807. doi: 10.1073/pnas.90.22.10803. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. McKenzie S. J., Marks P. J., Lam T., Morgan J., Panicali D. L., Trimpe K. L., Carney W. P. Generation and characterization of monoclonal antibodies specific for the human neu oncogene product, p185. Oncogene. 1989 May;4(5):543–548. [PubMed] [Google Scholar]
  29. Panayotou G., End P., Aumailley M., Timpl R., Engel J. Domains of laminin with growth-factor activity. Cell. 1989 Jan 13;56(1):93–101. doi: 10.1016/0092-8674(89)90987-2. [DOI] [PubMed] [Google Scholar]
  30. Parham P., Barnstable C. J., Bodmer W. F. Use of a monoclonal antibody (W6/32) in structural studies of HLA-A,B,C, antigens. J Immunol. 1979 Jul;123(1):342–349. [PubMed] [Google Scholar]
  31. Peles E., Bacus S. S., Koski R. A., Lu H. S., Wen D., Ogden S. G., Levy R. B., Yarden Y. Isolation of the neu/HER-2 stimulatory ligand: a 44 kd glycoprotein that induces differentiation of mammary tumor cells. Cell. 1992 Apr 3;69(1):205–216. doi: 10.1016/0092-8674(92)90131-u. [DOI] [PubMed] [Google Scholar]
  32. Pellegrini R., Centis F., Martignone S., Mastroianni A., Tagliabue E., Tosi E., Ménard S., Colnaghi M. I. Characterization of a monoclonal antibody directed against the epidermal growth factor receptor binding site. Cancer Immunol Immunother. 1991;34(1):37–42. doi: 10.1007/BF01741322. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Pellegrini R., Martignone S., Tagliabue E., Belotti D., Bufalino R., Cascinelli N., Ménard S., Colnaghi M. I. Prognostic significance of laminin production in relation with its receptor expression in human breast carcinomas. Breast Cancer Res Treat. 1995 Aug;35(2):195–199. doi: 10.1007/BF00668209. [DOI] [PubMed] [Google Scholar]
  34. 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]
  35. 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]
  36. Rilke F., Colnaghi M. I., Cascinelli N., Andreola S., Baldini M. T., Bufalino R., Della Porta G., Ménard S., Pierotti M. A., Testori A. Prognostic significance of HER-2/neu expression in breast cancer and its relationship to other prognostic factors. Int J Cancer. 1991 Aug 19;49(1):44–49. doi: 10.1002/ijc.2910490109. [DOI] [PubMed] [Google Scholar]
  37. Samanta A., LeVea C. M., Dougall W. C., Qian X., Greene M. I. Ligand and p185c-neu density govern receptor interactions and tyrosine kinase activation. Proc Natl Acad Sci U S A. 1994 Mar 1;91(5):1711–1715. doi: 10.1073/pnas.91.5.1711. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Sasaki M., Kato S., Kohno K., Martin G. R., Yamada Y. Sequence of the cDNA encoding the laminin B1 chain reveals a multidomain protein containing cysteine-rich repeats. Proc Natl Acad Sci U S A. 1987 Feb;84(4):935–939. doi: 10.1073/pnas.84.4.935. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Sasaki M., Yamada Y. The laminin B2 chain has a multidomain structure homologous to the B1 chain. J Biol Chem. 1987 Dec 15;262(35):17111–17117. [PubMed] [Google Scholar]
  40. 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]
  41. Sliwkowski M. X., Schaefer G., Akita R. W., Lofgren J. A., Fitzpatrick V. D., Nuijens A., Fendly B. M., Cerione R. A., Vandlen R. L., Carraway K. L., 3rd Coexpression of erbB2 and erbB3 proteins reconstitutes a high affinity receptor for heregulin. J Biol Chem. 1994 May 20;269(20):14661–14665. [PubMed] [Google Scholar]
  42. Stancovski I., Hurwitz E., Leitner O., Ullrich A., Yarden Y., Sela M. Mechanistic aspects of the opposing effects of monoclonal antibodies to the ERBB2 receptor on tumor growth. Proc Natl Acad Sci U S A. 1991 Oct 1;88(19):8691–8695. doi: 10.1073/pnas.88.19.8691. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Tagliabue E., Centis F., Campiglio M., Mastroianni A., Martignone S., Pellegrini R., Casalini P., Lanzi C., Ménard S., Colnaghi M. I. Selection of monoclonal antibodies which induce internalization and phosphorylation of p185HER2 and growth inhibition of cells with HER2/NEU gene amplification. Int J Cancer. 1991 Apr 1;47(6):933–937. doi: 10.1002/ijc.2910470625. [DOI] [PubMed] [Google Scholar]
  44. Tarakhovsky A., Zaichuk T., Prassolov V., Butenko Z. A. A 25 kDa polypeptide is the ligand for p185neu and is secreted by activated macrophages. Oncogene. 1991 Dec;6(12):2187–2196. [PubMed] [Google Scholar]
  45. Tzahar E., Levkowitz G., Karunagaran D., Yi L., Peles E., Lavi S., Chang D., Liu N., Yayon A., Wen D. ErbB-3 and ErbB-4 function as the respective low and high affinity receptors of all Neu differentiation factor/heregulin isoforms. J Biol Chem. 1994 Oct 7;269(40):25226–25233. [PubMed] [Google Scholar]
  46. Wen D., Peles E., Cupples R., Suggs S. V., Bacus S. S., Luo Y., Trail G., Hu S., Silbiger S. M., Levy R. B. Neu differentiation factor: a transmembrane glycoprotein containing an EGF domain and an immunoglobulin homology unit. Cell. 1992 May 1;69(3):559–572. doi: 10.1016/0092-8674(92)90456-m. [DOI] [PubMed] [Google Scholar]
  47. Yarden Y., Weinberg R. A. Experimental approaches to hypothetical hormones: detection of a candidate ligand of the neu protooncogene. Proc Natl Acad Sci U S A. 1989 May;86(9):3179–3183. doi: 10.1073/pnas.86.9.3179. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Zschiesche W., Schönborn I., Minguillon C., Spitzer E. Significance of immunohistochemical c-erbB-2 product localization pattern for prognosis of primary human breast cancer. Cancer Lett. 1994 Jun 15;81(1):89–94. doi: 10.1016/0304-3835(94)90169-4. [DOI] [PubMed] [Google Scholar]

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

RESOURCES