Evaluation of Smad2/3 and Smad4 as inhibitors of estrogens and Ski protein as a predictive factor in T1, T2 N0 breast carcinomas

Abstract

1543 Background: Smad proteins are TGF-β intracellular substrates, and Ski protein is a negative regulator of TGF-pathway. Tamoxifen's inhibition in breast cancer cells is mediated through TGF-β and Smad proteins. The purpose of our study was to investigate the activation of Smad2/3, Smad4, and Ski proteins in breast carcinomas and correlate their expression with each other and with hormonal receptors, as well as with other clinicopathological parameters such as the tumor size and grade, and the Distant Disease Free and the Overall Survival. Methods: One hundred forty-seven paraffin-embedded specimens from 22 in situ and 125 invasive ductal node-negative carcinomas were used, for which we had a mean follow-up time of 96 months. ER and PR status, as well as the expression of Smad2/3, Smad4, and Ski proteins were evaluated using immunohistochemistry. Staining of 5% of the tumor cells was adopted as a threshold. SPSS13 for windows was used for the statistical analysis of the results. Results: Smad2/3 and Smad4 were strongly correlated with each other (p < 0,001) and inversely correlated with patients’ DDFS (Kaplan-Meier plots, p = 0,004 for Smad2/3 and p = 0,026 for Smad4) and OS (Kaplan-Meier plots, p = 0,034 for Smad2/3 and p = 0,017 for Smad4). Smad2/3 was proved to be an independent prognostic factor in grade 1 tumors, while Smad4 was inversely correlated with PR expression (p = 0,028) and had a strong prognostic value in ER+ tumors (p = 0,02). Ski protein had a strong association with tumor grade (p < 0.001) and was found to be an independent prognostic factor in Cox regression analysis (p = 0,006, exp(B) = 4,98). Conclusions: Smad 2/3 and Smad 4 not only are tumor suppressor molecules, but also inhibit ER dependent gene expression. This inhibition is lost when Smad's expression is reduced, and that is a potent explanation for Smad 4 prognostic value in ER positive tumors. Moreover the correlation with PR expression, may be due to the fact that PR is an indicator of ER pathway's integrity and also to PR's enallaktiki activation by ER-β. From the other hand, Ski protein acts as an oncogene in breast carcinogenesis and contributes to the development of a more aggressive tumor phenotype. No significant financial relationships to disclose.