Thrombospondin-1 and -2 in node-negative breast cancer: correlation with angiogenic factors, p53, cathepsin D, hormone receptors and prognosis.
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.
Gasparini
G
G
Division of Medical Oncology, Azienda Complesso Ospedaliero 'San Filippo Neri', Rome, Italy.
Toi
M
M
Biganzoli
E
E
Dittadi
R
R
Fanelli
M
M
Morabito
A
A
Boracchi
P
P
Gion
M
M
D014408:Biomarkers, Tumor / Q000032:analysis*; D001943:Breast Neoplasms / Q000737:chemistry* / Q000473:pathology; D002402:Cathepsin D / Q000032:analysis*; D003600:Cytosol / Q000737:chemistry; D016228:Endothelial Growth Factors / Q000032:analysis*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008222:Lymphokines / Q000032:analysis*; D009389:Neovascularization, Pathologic / Q000378:metabolism; D011237:Predictive Value of Tests; D011379:Prognosis; D016016:Proportional Hazards Models; D011960:Receptors, Estrogen / Q000032:analysis*; D011980:Receptors, Progesterone / Q000032:analysis*; D019700:Thrombospondin 1 / Q000032:analysis; D019699:Thrombospondins / Q000032:analysis*; D013939:Thymidine Phosphorylase / Q000032:analysis; D016159:Tumor Suppressor Protein p53 / Q000032:analysis*; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D014408:Biomarkers, Tumor; D016228:Endothelial Growth Factors; D008222:Lymphokines; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D019700:Thrombospondin 1; D019699:Thrombospondins; D016159:Tumor Suppressor Protein p53; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D013939:Thymidine Phosphorylase; D002402:Cathepsin D