Enhanced mRNA expression of tissue inhibitor of metalloproteinase-1 (TIMP-1) in breast carcinomas is correlated with adverse prognosis

J Pathol. 2002 Jul;197(3):307-13. doi: 10.1002/path.1129.


Tissue inhibitor of metalloproteinase-1 (TIMP-1) has emerged as a multifunctional protein with the contrasting activities of inhibiting tissue-degrading enzymes and promoting cellular growth. In an attempt to elucidate the clinical significance of TIMP-1 in breast cancer, the expression of TIMP-1 mRNA was evaluated in 117 invasive breast carcinomas by mRNA in situ hybridization, in correlation with clinicopathological parameters, immunohistochemical prognostic factors (Ki-67, c-erb-B-2, bcl-2) and clinical outcome. TIMP-1 was detected in stromal cells in areas within the tumours and at the tumour margin. High TIMP-1 mRNA expression in the marginal portion of the tumours was significantly correlated with lymph node metastasis (p<0.05) and c-erbB-2 expression (p<0.05). On the other hand, increased TIMP-1 mRNA expression within the tumours showed a statistically significant correlation with ER detection (p<0.01). Multivariate analysis revealed worse survival for patients with high TIMP-1 mRNA expression in the marginal portion of the tumours; the subgroup of these patients co-expressing high levels of TIMP-1 mRNA within the tumours as well had even worse survival (p=0.042). In conclusion, our data support the multifunctional role of TIMP-1, particularly its growth-promoting activity, on the basis of its significant correlation with lymph node metastasis and adverse prognosis. In addition to the latter property, a probable association of TIMP-1 with tumour cell differentiation is suggested by its topographical correlation with ER detection.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Biomarkers / analysis
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / mortality
  • Carcinoma, Ductal, Breast / metabolism*
  • Carcinoma, Ductal, Breast / mortality
  • Carcinoma, Lobular / metabolism*
  • Carcinoma, Lobular / mortality
  • Chi-Square Distribution
  • Female
  • Humans
  • Immunohistochemistry / methods
  • In Situ Hybridization / methods
  • Ki-67 Antigen / analysis
  • Lymphatic Metastasis
  • Middle Aged
  • Proto-Oncogene Proteins c-bcl-2 / analysis
  • RNA, Messenger / metabolism*
  • Receptor, ErbB-2 / analysis
  • Ribonuclease, Pancreatic
  • Survival Rate
  • Tissue Inhibitor of Metalloproteinase-1 / genetics*


  • Biomarkers
  • Ki-67 Antigen
  • Proto-Oncogene Proteins c-bcl-2
  • RNA, Messenger
  • Tissue Inhibitor of Metalloproteinase-1
  • Receptor, ErbB-2
  • Ribonuclease, Pancreatic