Skip to main content
NCBI home page
British Journal of Cancer logoLink to British Journal of Cancer
. 2001 Jun;84(11):1488–1496. doi: 10.1054/bjoc.2001.1810

Overexpression of matrix-metalloproteinase-9 in human breast cancer: a potential favourable indicator in node-negativeatients

A Scorilas 1,5,6, A Karameris 5, N Arnogiannaki 2, A Ardavanis 3, P Bassilopoulos 4, T Trangas 1, M Talieri 1
PMCID: PMC2363667  PMID: 11384099

Abstract

Matrix metalloprotease-9 (MMP-9; 92 kDa type IV collaganase, gelatinase B) is regarded as, important for degradation of the basement membrane and extracellular matrix during cancer invasion and other tissue-remodelling events. In this study we evaluate the prognostic value of MMP-9, by immunoperoxidase staining in a series of 210 breast cancer tissues. The results were quantitated using the HSCORE system, which consider both staining intensity and the percentage of cells stained at given intensities. MMP-9 status was compared with the concentration of cytosolic Cathepsin-D and with other established prognostic factors, in terms of disease free survival and overall survival. The median follow-up period was 62 months. MMP-9 staining was observed primarily in cancer cells, and to a lesser degree in surrounding stromal cells. MMP-9 expression was not detected in normal breast tissue. Levels of MMP-9 expression below the cut-off point were more frequently observed in larger (P = 0.014), invasive ductal histologic (P = 0.037), progesterone receptor (PR)-negative and PR-strong positive tumours (P< 0.001), as well as samples belonging to patients with stage III-IV disease (P = 0.009) and age 45–55 years (P = 0.011). In univariate analysis, node-negative breast cancer patients with tumors positive for MMP-9 had a considerable reduction in risk for relapse (RR = 0.45;P = 0.039) or death (RR = 0.32;P = 0.009). Multivariate analysis indicated that MMP-9 status was an independent favourable predictor of OS (RR = 0.47;P = 0.034) in node-negative but not in node-positive patients. Our results suggest that MMP-9 may be an independent favourable prognostic factor in node-negative breast cancer patients. The overexpression of MMP-9 in breast cancer may be also used as a marker to subdivide node negative breast cancer patients in order to determine the optimal treatment modality. © 2001 Cancer Research Campaign http://www.bjcancer.com

Keywords: MMP-9, breast cancer, prognostic factor

Full Text

The Full Text of this article is available as a PDF (360.7 KB).

Selected References

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

  1. Ardavanis A., Scorilas A., Amanatidou A., Gerakini F., Missitzis I., Garoufali A., Pissakas G., Pateras C., Apostolikas N., Rigatos G. Cathepsin D concentration in tumor cytosols improves the accuracy of prognostic evaluation of primary breast cancer. Anticancer Res. 1997 Mar-Apr;17(2B):1405–1409. [PubMed] [Google Scholar]
  2. Bajou K., Noël A., Gerard R. D., Masson V., Brunner N., Holst-Hansen C., Skobe M., Fusenig N. E., Carmeliet P., Collen D. Absence of host plasminogen activator inhibitor 1 prevents cancer invasion and vascularization. Nat Med. 1998 Aug;4(8):923–928. doi: 10.1038/nm0898-923. [DOI] [PubMed] [Google Scholar]
  3. Benaud C., Dickson R. B., Thompson E. W. Roles of the matrix metalloproteinases in mammary gland development and cancer. Breast Cancer Res Treat. 1998 Jul;50(2):97–116. doi: 10.1023/a:1006061115909. [DOI] [PubMed] [Google Scholar]
  4. Bianchi E., Cohen R. L., Dai A., Thor A. T., Shuman M. A., Smith H. S. Immunohistochemical localization of the plasminogen activator inhibitor-1 in breast cancer. Int J Cancer. 1995 Mar 3;60(5):597–603. doi: 10.1002/ijc.2910600505. [DOI] [PubMed] [Google Scholar]
  5. Blavier L., DeClerck Y. A. Tissue inhibitor of metalloproteinases-2 is expressed in the interstitial matrix in adult mouse organs and during embryonic development. Mol Biol Cell. 1997 Aug;8(8):1513–1527. doi: 10.1091/mbc.8.8.1513. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Daidone M. G., Silvestrini R., D'Errico A., Di Fronzo G., Benini E., Mancini A. M., Garbisa S., Liotta L. A., Grigioni W. F. Laminin receptors, collagenase IV and prognosis in node-negative breast cancers. Int J Cancer. 1991 Jun 19;48(4):529–532. doi: 10.1002/ijc.2910480409. [DOI] [PubMed] [Google Scholar]
  7. Duffy M. J., Blaser J., Duggan C., McDermott E., O'Higgins N., Fennelly J. J., Tschesche H. Assay of matrix metalloproteases types 8 and 9 by ELISA in human breast cancer. Br J Cancer. 1995 May;71(5):1025–1028. doi: 10.1038/bjc.1995.197. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Elashry-Stowers D., Zava D. T., Speers W. C., Edwards D. P. Immunocytochemical localization of progesterone receptors in breast cancer with anti-human receptor monoclonal antibodies. Cancer Res. 1988 Nov 15;48(22):6462–6474. [PubMed] [Google Scholar]
  9. Fridman R., Toth M., Peña D., Mobashery S. Activation of progelatinase B (MMP-9) by gelatinase A (MMP-2). Cancer Res. 1995 Jun 15;55(12):2548–2555. [PubMed] [Google Scholar]
  10. Garbett E. A., Reed M. W., Brown N. J. Proteolysis in human breast and colorectal cancer. Br J Cancer. 1999 Sep;81(2):287–293. doi: 10.1038/sj.bjc.6690689. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Hanemaaijer R., Sier C. F., Visser H., Scholte L., van Lent N., Toet K., Hoekman K., Verheijen J. H. MMP-9 activity in urine from patients with various tumors, as measured by a novel MMP activity assay using modified urokinase as a substrate. Ann N Y Acad Sci. 1999 Jun 30;878:141–149. doi: 10.1111/j.1749-6632.1999.tb07680.x. [DOI] [PubMed] [Google Scholar]
  12. Heppner K. J., Matrisian L. M., Jensen R. A., Rodgers W. H. Expression of most matrix metalloproteinase family members in breast cancer represents a tumor-induced host response. Am J Pathol. 1996 Jul;149(1):273–282. [PMC free article] [PubMed] [Google Scholar]
  13. Hewitt R., Danø K. Stromal cell expression of components of matrix-degrading protease systems in human cancer. Enzyme Protein. 1996;49(1-3):163–173. doi: 10.1159/000468623. [DOI] [PubMed] [Google Scholar]
  14. Jonat C., Rahmsdorf H. J., Park K. K., Cato A. C., Gebel S., Ponta H., Herrlich P. Antitumor promotion and antiinflammation: down-modulation of AP-1 (Fos/Jun) activity by glucocorticoid hormone. Cell. 1990 Sep 21;62(6):1189–1204. doi: 10.1016/0092-8674(90)90395-u. [DOI] [PubMed] [Google Scholar]
  15. Jones J. L., Glynn P., Walker R. A. Expression of MMP-2 and MMP-9, their inhibitors, and the activator MT1-MMP in primary breast carcinomas. J Pathol. 1999 Oct;189(2):161–168. doi: 10.1002/(SICI)1096-9896(199910)189:2<161::AID-PATH406>3.0.CO;2-2. [DOI] [PubMed] [Google Scholar]
  16. Karameris A., Panagou P., Tsilalis T., Bouros D. Association of expression of metalloproteinases and their inhibitors with the metastatic potential of squamous-cell lung carcinomas. A molecular and immunohistochemical study. Am J Respir Crit Care Med. 1997 Dec;156(6):1930–1936. doi: 10.1164/ajrccm.156.6.9612046. [DOI] [PubMed] [Google Scholar]
  17. Kute T. E., Huske M. S., Shore A., Rhyne A. L. Improvements in steroid receptor assays including rapid computer analysis of data. Anal Biochem. 1980 Apr;103(2):272–279. doi: 10.1016/0003-2697(80)90609-0. [DOI] [PubMed] [Google Scholar]
  18. Le Doussal V., Tubiana-Hulin M., Friedman S., Hacene K., Spyratos F., Brunet M. Prognostic value of histologic grade nuclear components of Scarff-Bloom-Richardson (SBR). An improved score modification based on a multivariate analysis of 1262 invasive ductal breast carcinomas. Cancer. 1989 Nov 1;64(9):1914–1921. doi: 10.1002/1097-0142(19891101)64:9<1914::aid-cncr2820640926>3.0.co;2-g. [DOI] [PubMed] [Google Scholar]
  19. Magklara A., Scorilas A., Stephan C., Kristiansen G. O., Hauptmann S., Jung K., Diamandis E. P. Decreased concentrations of prostate-specific antigen and human glandular kallikrein 2 in malignant versus nonmalignant prostatic tissue. Urology. 2000 Sep 1;56(3):527–532. doi: 10.1016/s0090-4295(00)00621-x. [DOI] [PubMed] [Google Scholar]
  20. Mira E., Mañes S., Lacalle R. A., Márquez G., Martínez-A C. Insulin-like growth factor I-triggered cell migration and invasion are mediated by matrix metalloproteinase-9. Endocrinology. 1999 Apr;140(4):1657–1664. doi: 10.1210/endo.140.4.6623. [DOI] [PubMed] [Google Scholar]
  21. Nelson A. R., Fingleton B., Rothenberg M. L., Matrisian L. M. Matrix metalloproteinases: biologic activity and clinical implications. J Clin Oncol. 2000 Mar;18(5):1135–1149. doi: 10.1200/JCO.2000.18.5.1135. [DOI] [PubMed] [Google Scholar]
  22. Nielsen B. S., Sehested M., Kjeldsen L., Borregaard N., Rygaard J., Danø K. Expression of matrix metalloprotease-9 in vascular pericytes in human breast cancer. Lab Invest. 1997 Oct;77(4):345–355. [PubMed] [Google Scholar]
  23. Nielsen B. S., Sehested M., Timshel S., Pyke C., Danø K. Messenger RNA for urokinase plasminogen activator is expressed in myofibroblasts adjacent to cancer cells in human breast cancer. Lab Invest. 1996 Jan;74(1):168–177. [PubMed] [Google Scholar]
  24. Nielsen B. S., Timshel S., Kjeldsen L., Sehested M., Pyke C., Borregaard N., Danø K. 92 kDa type IV collagenase (MMP-9) is expressed in neutrophils and macrophages but not in malignant epithelial cells in human colon cancer. Int J Cancer. 1996 Jan 3;65(1):57–62. doi: 10.1002/(SICI)1097-0215(19960103)65:1<57::AID-IJC10>3.0.CO;2-F. [DOI] [PubMed] [Google Scholar]
  25. Pacheco M. M., Mourão M., Mantovani E. B., Nishimoto I. N., Brentani M. M. Expression of gelatinases A and B, stromelysin-3 and matrilysin genes in breast carcinomas: clinico-pathological correlations. Clin Exp Metastasis. 1998 Oct;16(7):577–585. doi: 10.1023/a:1006580415796. [DOI] [PubMed] [Google Scholar]
  26. Ree A. H., Bjørnland K., Brünner N., Johansen H. T., Pedersen K. B., Aasen A. O., Fodstad O. Regulation of tissue-degrading factors and in vitro invasiveness in progression of breast cancer cells. Clin Exp Metastasis. 1998 Apr;16(3):205–215. doi: 10.1023/a:1006584624061. [DOI] [PubMed] [Google Scholar]
  27. Remacle A. G., Noël A., Duggan C., McDermott E., O'Higgins N., Foidart J. M., Duffy M. J. Assay of matrix metalloproteinases types 1, 2, 3 and 9 in breast cancer. Br J Cancer. 1998 Mar;77(6):926–931. doi: 10.1038/bjc.1998.153. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Rha S. Y., Kim J. H., Roh J. K., Lee K. S., Min J. S., Kim B. S., Chung H. C. Sequential production and activation of matrix-metalloproteinase-9 (MMP-9) with breast cancer progression. Breast Cancer Res Treat. 1997 Apr;43(2):175–181. doi: 10.1023/a:1005701231871. [DOI] [PubMed] [Google Scholar]
  29. Rha S. Y., Yang W. I., Kim J. H., Roh J. K., Min J. S., Lee K. S., Kim B. S., Chung H. C. Different expression patterns of MMP-2 and MMP-9 in breast cancer. Oncol Rep. 1998 Jul-Aug;5(4):875–879. doi: 10.3892/or.5.4.875. [DOI] [PubMed] [Google Scholar]
  30. Salamonsen L. A., Butt A. R., Hammond F. R., Garcia S., Zhang J. Production of endometrial matrix metalloproteinases, but not their tissue inhibitors, is modulated by progesterone withdrawal in an in vitro model for menstruation. J Clin Endocrinol Metab. 1997 May;82(5):1409–1415. doi: 10.1210/jcem.82.5.3920. [DOI] [PubMed] [Google Scholar]
  31. Scorilas A., Black M. H., Talieri M., Diamandis E. P. Genomic organization, physical mapping, and expression analysis of the human protein arginine methyltransferase 1 gene. Biochem Biophys Res Commun. 2000 Nov 19;278(2):349–359. doi: 10.1006/bbrc.2000.3807. [DOI] [PubMed] [Google Scholar]
  32. Scorilas A., Diamandis E. P., Levesque M. A., Papanastasiou-Diamandi A., Khosravi M. J., Giai M., Ponzone R., Roagna R., Sismondi P., López-Otin C. Immunoenzymatically determined pepsinogen C concentration in breast tumor cytosols: an independent favorable prognostic factor in node-positive patients. Clin Cancer Res. 1999 Jul;5(7):1778–1785. [PubMed] [Google Scholar]
  33. Scorilas A., Talieri M., Ardavanis A., Courtis N., Dimitriadis E., Yotis J., Tsiapalis C. M., Trangas T. Polyadenylate polymerase enzymatic activity in mammary tumor cytosols: A new independent prognostic marker in primary breast cancer. Cancer Res. 2000 Oct 1;60(19):5427–5433. [PubMed] [Google Scholar]
  34. Scorilas A., Trangas T., Yotis J., Pateras C., Talieri M. Determination of c-myc amplification and overexpression in breast cancer patients: evaluation of its prognostic value against c-erbB-2, cathepsin-D and clinicopathological characteristics using univariate and multivariate analysis. Br J Cancer. 1999 Dec;81(8):1385–1391. doi: 10.1038/sj.bjc.6693404. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Scorilas A., Yotis J., Gouriotis D., Keramopoulos A., Ampela K., Trangas T., Talieri M. Cathepsin-D and c-erb-B 2 have an additive prognostic value for breast cancer patients. Anticancer Res. 1993 Sep-Oct;13(5C):1895–1900. [PubMed] [Google Scholar]
  36. Scorilas A., Yotis J., Pateras C., Trangas T., Talieri M. Predictive value of c-erbB-2 and cathepsin-D for Greek breast cancer patients using univariate and multivariate analysis. Clin Cancer Res. 1999 Apr;5(4):815–821. [PubMed] [Google Scholar]
  37. Scorilas A., Yotis J., Stravolemos K., Gouriotis D., Keramopoulos A., Ampela K., Talieri M., Trangas T. c-erbB-2 overexpression may be used as an independent prognostic factor for breast cancer patients. Anticancer Res. 1995 Jul-Aug;15(4):1543–1547. [PubMed] [Google Scholar]
  38. Sugiura Y., Shimada H., Seeger R. C., Laug W. E., DeClerck Y. A. Matrix metalloproteinases-2 and -9 are expressed in human neuroblastoma: contribution of stromal cells to their production and correlation with metastasis. Cancer Res. 1998 May 15;58(10):2209–2216. [PubMed] [Google Scholar]
  39. Takeha S., Fujiyama Y., Bamba T., Sorsa T., Nagura H., Ohtani H. Stromal expression of MMP-9 and urokinase receptor is inversely associated with liver metastasis and with infiltrating growth in human colorectal cancer: a novel approach from immune/inflammatory aspect. Jpn J Cancer Res. 1997 Jan;88(1):72–81. doi: 10.1111/j.1349-7006.1997.tb00304.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Thorpe S. M., Christensen I. J., Rasmussen B. B., Rose C. Short recurrence-free survival associated with high oestrogen receptor levels in the natural history of postmenopausal, primary breast cancer. Eur J Cancer. 1993;29A(7):971–977. doi: 10.1016/s0959-8049(05)80204-7. [DOI] [PubMed] [Google Scholar]
  41. Tryggvason K., Höyhtyä M., Pyke C. Type IV collagenases in invasive tumors. Breast Cancer Res Treat. 1993;24(3):209–218. doi: 10.1007/BF01833261. [DOI] [PubMed] [Google Scholar]
  42. Visscher D. W., Höyhtyä M., Ottosen S. K., Liang C. M., Sarkar F. H., Crissman J. D., Fridman R. Enhanced expression of tissue inhibitor of metalloproteinase-2 (TIMP-2) in the stroma of breast carcinomas correlates with tumor recurrence. Int J Cancer. 1994 Nov 1;59(3):339–344. doi: 10.1002/ijc.2910590308. [DOI] [PubMed] [Google Scholar]
  43. Vizoso F., Sánchez L. M., Díez-Itza I., Merino A. M., López-Otín C. Pepsinogen C is a new prognostic marker in primary breast cancer. J Clin Oncol. 1995 Jan;13(1):54–61. doi: 10.1200/JCO.1995.13.1.54. [DOI] [PubMed] [Google Scholar]
  44. Yan S., Sameni M., Sloane B. F. Cathepsin B and human tumor progression. Biol Chem. 1998 Feb;379(2):113–123. [PubMed] [Google Scholar]
  45. Yousef G. M., Scorilas A., Diamandis E. P. Genomic organization, mapping, tissue expression, and hormonal regulation of trypsin-like serine protease (TLSP PRSS20), a new member of the human kallikrein gene family. Genomics. 2000 Jan 1;63(1):88–96. doi: 10.1006/geno.1999.6072. [DOI] [PubMed] [Google Scholar]
  46. Yousef G. M., Scorilas A., Jung K., Ashworth L. K., Diamandis E. P. Molecular cloning of the human kallikrein 15 gene (KLK15). Up-regulation in prostate cancer. J Biol Chem. 2001 Jan 5;276(1):53–61. doi: 10.1074/jbc.M005432200. [DOI] [PubMed] [Google Scholar]
  47. Yu H., Levesque M. A., Clark G. M., Diamandis E. P. Prognostic value of prostate-specific antigen for women with breast cancer: a large United States cohort study. Clin Cancer Res. 1998 Jun;4(6):1489–1497. [PubMed] [Google Scholar]
  48. Yu Q., Stamenkovic I. Localization of matrix metalloproteinase 9 to the cell surface provides a mechanism for CD44-mediated tumor invasion. Genes Dev. 1999 Jan 1;13(1):35–48. doi: 10.1101/gad.13.1.35. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Zucker S., Hymowitz M., Conner C., Zarrabi H. M., Hurewitz A. N., Matrisian L., Boyd D., Nicolson G., Montana S. Measurement of matrix metalloproteinases and tissue inhibitors of metalloproteinases in blood and tissues. Clinical and experimental applications. Ann N Y Acad Sci. 1999 Jun 30;878:212–227. doi: 10.1111/j.1749-6632.1999.tb07687.x. [DOI] [PubMed] [Google Scholar]

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

RESOURCES