The favorable prognostic impact of tissue inhibitor of matrix metalloproteinases-1 protein overexpression in breast cancer cells

APMIS. 2003 Nov;111(11):1027-36. doi: 10.1111/j.1600-0463.2003.apm1111105.x.


The tissue inhibitor of metalloproteinases-1 (TIMP1) inhibits tumor cell invasion and metastasis in experimental models; in addition, TIMP1 is supposed to possess another important function, cell growth promotion. The potential prognostic significance of TIMP1 in breast cancer remains unclear. We evaluated the significance of the immunohistochemical expression of TIMP1 in a well-documented series of 133 infiltrating breast carcinomas by examining any possible statistical association between this expression and numerous clinicopathological parameters as well as patients' disease-free interval. TIMP1 was generally expressed in both stromal and cancer cells in our specimens. TIMP1 was overexpressed in cancer cells of 60.15% of all cases. Tumors of high histological and nuclear grade were found to overexpress TIMP1 less frequently than the rest (p=0.003 and p=0.057, respectively). Interestingly, TIMP1 overexpression was inversely associated with cell proliferation, the latter being evidenced by Ki67 immunoreactivity (p=0.028). TIMP1 immunostaining was in parallel with metalloproteinase-2 (MMP2) immunoexpression in both cancer and stromal cells. Multivariate analysis disclosed that TIMP1 overexpression in cancer cells was an independent determining factor for prognosis (p=0.006); TIMP1 overexpression in malignant cells appeared to correlate with favorable outcome, particularly in patients with lack of nodal metastases and in patients with MMP2-negative immunophenotype (p=0.0252). The upregulation of TIMP1 cancer cell expression in breast cancer may suggest that this marker has a multifunctional role apart from that of metalloproteinase inhibitor since it was found to be related to malignant cells' differentiation and proliferation. TIMP1 overexpression in cancer cells appears for the first time to be a promising indicator of favorable prognosis in breast cancer.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biomarkers, Tumor / analysis*
  • Biomarkers, Tumor / metabolism
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Carcinoma, Ductal, Breast / metabolism*
  • Carcinoma, Ductal, Breast / pathology
  • Carcinoma, Lobular / metabolism*
  • Carcinoma, Lobular / pathology
  • Female
  • Humans
  • Immunohistochemistry
  • Matrix Metalloproteinase 2 / metabolism
  • Multivariate Analysis
  • Neoplasm Invasiveness
  • Neoplasm Staging
  • Prognosis
  • Stromal Cells / metabolism
  • Stromal Cells / pathology
  • Survival Rate
  • Tissue Inhibitor of Metalloproteinase-1 / analysis*
  • Tissue Inhibitor of Metalloproteinase-1 / metabolism


  • Biomarkers, Tumor
  • Tissue Inhibitor of Metalloproteinase-1
  • Matrix Metalloproteinase 2