Thrombospondin-1 and -2 in node-negative breast cancer: correlation with angiogenic factors, p53, cathepsin D, hormone receptors and prognosis

Oncology. 2001;60(1):72-80. doi: 10.1159/000055300.


Objective: Thrombospondins (TSP(s)) are a multigene family of five secreted glycoproteins involved in the regulation of cell proliferation, adhesion and migration. Two members of the TSP family, namely TSP-1 and TSP-2, are also naturally occurring inhibitors of angiogenesis. The aim of the present study was to determine the prognostic significance of the determination of TSP-1 and -2 and their correlation with the angiogenic peptides vascular endothelial growth factor (VEGF) and thymidine phosphorylase (TP), as well as with other biological and clinicopathological features investigated.

Methods: We evaluated a series of 168 women with node-negative breast cancer with a median follow-up period of 66 months, not treated with adjuvant therapy. The cytosolic levels of TSP-1 and -2 were determined in the primary tumour by a commercially available immunometric assay.

Results: We found that 166 tested tumours had measurable levels of TSP-1 and -2 protein (median value 5.978, range 0.579-31.410 ng/mg of protein). On the basis of Spearman's rank correlation coefficient, a weak inverse association of TSP-1 and -2 with tumour size and cathepsin D was found. Moreover, principal component analysis on ranks evidenced a poor association between TSP-1 and -2, VEGF and TP. The results of the clinical outcome were analysed by both univariate and multivariate [for relapse-free survival (RFS) only]) Cox regression models. TSP-1 and -2 were not significant prognostic factors in univariate analysis for either RFS (p = 0.427) or overall survival (p = 0.069). To investigate the 'angiogenic balance hypothesis', bivariate analyses were performed to investigate the interactions of TSP-1 and -2 with VEGF, TP or p53, but none were included in the selected models. Finally, in multivariate analysis for RFS a baseline model, previously defined in a larger case series and inclusive of VEGF, TP and their interaction was adopted. It was highly significant (p = 0.002, Harrell c statistic value of 0.703); but when TSP-1 and -2 were added, their contribution was negligible (p = 0.731, Harrell c statistic value of 0.705).

Conclusions: The results of this study suggest that TSP-1 and -2 do not provide additional prognostic contribution to the joint effects of VEGF and TP. In the series of node-negative breast cancer patients investigated, determination of the angiogenic peptides VEGF and TP gave significant prognostic information. On the contrary, TSP-1 and -2, potential naturally occurring negative regulators of angiogenesis, lacked prognostic value.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biomarkers, Tumor / analysis*
  • Breast Neoplasms / chemistry*
  • Breast Neoplasms / pathology
  • Cathepsin D / analysis*
  • Cytosol / chemistry
  • Endothelial Growth Factors / analysis*
  • Female
  • Humans
  • Immunohistochemistry
  • Lymphokines / analysis*
  • Neovascularization, Pathologic / metabolism
  • Predictive Value of Tests
  • Prognosis
  • Proportional Hazards Models
  • Receptors, Estrogen / analysis*
  • Receptors, Progesterone / analysis*
  • Thrombospondin 1 / analysis
  • Thrombospondins / analysis*
  • Thymidine Phosphorylase / analysis
  • Tumor Suppressor Protein p53 / analysis*
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors


  • Biomarkers, Tumor
  • Endothelial Growth Factors
  • Lymphokines
  • Receptors, Estrogen
  • Receptors, Progesterone
  • Thrombospondin 1
  • Thrombospondins
  • Tumor Suppressor Protein p53
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors
  • Thymidine Phosphorylase
  • Cathepsin D