Skip to main content
British Journal of Cancer logoLink to British Journal of Cancer
. 1999 Feb;79(3-4):401–406. doi: 10.1038/sj.bjc.6690063

Role of thrombin receptor in breast cancer invasiveness

K P Henrikson 1,2, S L Salazar 1,2, J W Fenton II 1, B T Pentecost 1,2
PMCID: PMC2362433  PMID: 10027305

Abstract

Invasion, the ability of an epithelial cancer cell to detach from and move through a basement membrane, is a central process in tumour metastasis. Two components of invasion are proteolysis of extracellular matrix and cellular movement through it. A potential promoter of these two processes is thrombin, the serine proteinase derived from the ubiquitous plasma protein prothrombin. Thrombin promotes the invasion of MDA-MB231 breast tumour cells (a highly aggressive cell line) in an in vitro assay. Invasion by MDA-MB436 and MCF-7 cells, less aggressive cell lines, is not promoted by thrombin. Thrombin, added to the cells, is a stimulator of cellular movement; fibroblast-conditioned medium is the chemotaxin. Thrombin-promoted invasion is inhibited by hirudin. Stimulation of invasion is a receptor-mediated process that is mimicked by a thrombin receptor-activating peptide. Thrombin has no effect on chemotaxis in vitro. Thrombin receptor is detectable on the surface of MDA-MB231 cells, but not on the other two cell lines. Introduction of oestrogen receptors into MDA-MB231 cells by transfection with pHEO had no effect on thrombin receptor expression, in the presence or absence of oestradiol. This paper demonstrates that thrombin increases invasion by the aggressive breast cancer cell line MDA-MB231 by a thrombin receptor-dependent mechanism. © 1999 Cancer Research Campaign

Keywords: thrombin, breast cancer, thrombin receptor, invasive cancer, cell culture

Full Text

The Full Text of this article is available as a PDF (178.9 KB).

Selected References

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

  1. Arena C. S., Quirk S. M., Zhang Y. Q., Henrikson K. P. Rat uterine stromal cells: thrombin receptor and growth stimulation by thrombin. Endocrinology. 1996 Sep;137(9):3744–3749. doi: 10.1210/endo.137.9.8756541. [DOI] [PubMed] [Google Scholar]
  2. Azzam H. S., Arand G., Lippman M. E., Thompson E. W. Association of MMP-2 activation potential with metastatic progression in human breast cancer cell lines independent of MMP-2 production. J Natl Cancer Inst. 1993 Nov 3;85(21):1758–1764. doi: 10.1093/jnci/85.21.1758. [DOI] [PubMed] [Google Scholar]
  3. Bae S. N., Arand G., Azzam H., Pavasant P., Torri J., Frandsen T. L., Thompson E. W. Molecular and cellular analysis of basement membrane invasion by human breast cancer cells in Matrigel-based in vitro assays. Breast Cancer Res Treat. 1993;24(3):241–255. doi: 10.1007/BF01833264. [DOI] [PubMed] [Google Scholar]
  4. Brass L. F. Issues in the development of thrombin receptor antagonists. Thromb Haemost. 1995 Jul;74(1):499–505. [PubMed] [Google Scholar]
  5. Brass L. F., Manning D. R., Cichowski K., Abrams C. S. Signaling through G proteins in platelets: to the integrins and beyond. Thromb Haemost. 1997 Jul;78(1):581–589. [PubMed] [Google Scholar]
  6. Chenard M. P., O'Siorain L., Shering S., Rouyer N., Lutz Y., Wolf C., Basset P., Bellocq J. P., Duffy M. J. High levels of stromelysin-3 correlate with poor prognosis in patients with breast carcinoma. Int J Cancer. 1996 Dec 20;69(6):448–451. doi: 10.1002/(SICI)1097-0215(19961220)69:6<448::AID-IJC5>3.0.CO;2-4. [DOI] [PubMed] [Google Scholar]
  7. DeMichele M. A., Minnear F. L. Modulation of vascular endothelial permeability by thrombin. Semin Thromb Hemost. 1992;18(3):287–295. doi: 10.1055/s-2007-1002567. [DOI] [PubMed] [Google Scholar]
  8. Duhamel-Clérin E., Orvain C., Lanza F., Cazenave J. P., Klein-Soyer C. Thrombin receptor-mediated increase of two matrix metalloproteinases, MMP-1 and MMP-3, in human endothelial cells. Arterioscler Thromb Vasc Biol. 1997 Oct;17(10):1931–1938. doi: 10.1161/01.atv.17.10.1931. [DOI] [PubMed] [Google Scholar]
  9. Fidler I. J., Ellis L. M. The implications of angiogenesis for the biology and therapy of cancer metastasis. Cell. 1994 Oct 21;79(2):185–188. doi: 10.1016/0092-8674(94)90187-2. [DOI] [PubMed] [Google Scholar]
  10. Galis Z. S., Kranzhöfer R., Fenton J. W., 2nd, Libby P. Thrombin promotes activation of matrix metalloproteinase-2 produced by cultured vascular smooth muscle cells. Arterioscler Thromb Vasc Biol. 1997 Mar;17(3):483–489. doi: 10.1161/01.atv.17.3.483. [DOI] [PubMed] [Google Scholar]
  11. Gui G. P., Puddefoot J. R., Vinson G. P., Wells C. A., Carpenter R. Altered cell-matrix contact: a prerequisite for breast cancer metastasis? Br J Cancer. 1997;75(5):623–633. doi: 10.1038/bjc.1997.113. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Kranzhöfer R., Clinton S. K., Ishii K., Coughlin S. R., Fenton J. W., 2nd, Libby P. Thrombin potently stimulates cytokine production in human vascular smooth muscle cells but not in mononuclear phagocytes. Circ Res. 1996 Aug;79(2):286–294. doi: 10.1161/01.res.79.2.286. [DOI] [PubMed] [Google Scholar]
  13. Maemura M., Akiyama S. K., Woods V. L., Jr, Dickson R. B. Expression and ligand binding of alpha 2 beta 1 integrin on breast carcinoma cells. Clin Exp Metastasis. 1995 Jul;13(4):223–235. doi: 10.1007/BF00133478. [DOI] [PubMed] [Google Scholar]
  14. Nierodzik M. L., Bain R. M., Liu L. X., Shivji M., Takeshita K., Karpatkin S. Presence of the seven transmembrane thrombin receptor on human tumour cells: effect of activation on tumour adhesion to platelets and tumor tyrosine phosphorylation. Br J Haematol. 1996 Feb;92(2):452–457. doi: 10.1046/j.1365-2141.1996.d01-1494.x. [DOI] [PubMed] [Google Scholar]
  15. Price J. T., Bonovich M. T., Kohn E. C. The biochemistry of cancer dissemination. Crit Rev Biochem Mol Biol. 1997;32(3):175–253. doi: 10.3109/10409239709082573. [DOI] [PubMed] [Google Scholar]
  16. Shapiro S. S., McCord S. Prothrombin. Prog Hemost Thromb. 1978;4:177–209. [PubMed] [Google Scholar]
  17. Thompson E. W., Paik S., Brünner N., Sommers C. L., Zugmaier G., Clarke R., Shima T. B., Torri J., Donahue S., Lippman M. E. Association of increased basement membrane invasiveness with absence of estrogen receptor and expression of vimentin in human breast cancer cell lines. J Cell Physiol. 1992 Mar;150(3):534–544. doi: 10.1002/jcp.1041500314. [DOI] [PubMed] [Google Scholar]
  18. Thompson E. W., Yu M., Bueno J., Jin L., Maiti S. N., Palao-Marco F. L., Pulyaeva H., Tamborlane J. W., Tirgari R., Wapnir I. Collagen induced MMP-2 activation in human breast cancer. Breast Cancer Res Treat. 1994;31(2-3):357–370. doi: 10.1007/BF00666168. [DOI] [PubMed] [Google Scholar]
  19. Tora L., Mullick A., Metzger D., Ponglikitmongkol M., Park I., Chambon P. The cloned human oestrogen receptor contains a mutation which alters its hormone binding properties. EMBO J. 1989 Jul;8(7):1981–1986. doi: 10.1002/j.1460-2075.1989.tb03604.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Wojtukiewicz M. Z., Tang D. G., Ben-Josef E., Renaud C., Walz D. A., Honn K. V. Solid tumor cells express functional "tethered ligand" thrombin receptor. Cancer Res. 1995 Feb 1;55(3):698–704. [PubMed] [Google Scholar]
  21. Wojtukiewicz M. Z., Tang D. G., Ciarelli J. J., Nelson K. K., Walz D. A., Diglio C. A., Mammen E. F., Honn K. V. Thrombin increases the metastatic potential of tumor cells. Int J Cancer. 1993 Jul 9;54(5):793–806. doi: 10.1002/ijc.2910540514. [DOI] [PubMed] [Google Scholar]
  22. Zacharski L. R., Memoli V. A., Morain W. D., Schlaeppi J. M., Rousseau S. M. Cellular localization of enzymatically active thrombin in intact human tissues by hirudin binding. Thromb Haemost. 1995 May;73(5):793–797. [PubMed] [Google Scholar]
  23. Zacharski L. R., Wojtukiewicz M. Z., Costantini V., Ornstein D. L., Memoli V. A. Pathways of coagulation/fibrinolysis activation in malignancy. Semin Thromb Hemost. 1992 Jan;18(1):104–116. doi: 10.1055/s-2007-1002415. [DOI] [PubMed] [Google Scholar]

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

RESOURCES