Differential effect of the expression of TGF‐β pathway inhibitors, Smad‐7 and Ski, on invasive breast carcinomas: relation to biologic behavior

Abstract

The aim of our study was to investigate the expression of Smad-7 and Ski proteins in invasive breast carcinomas, to determine their clinicopathological value and their influence on carcinomas biologic behavior. Immunohistochemistry was applied on 150 invasive breast carcinomas to detect the expression of Smad-7 and Ski. Their correlation to clinicopathologic parameters and markers of metastasis was statistically processed using chi-squared test. Overall and disease-free survival was assessed using Kaplan-Meier test and log-rank statistics. Smad-7 was immunodetected in the cytoplasm of cancer cells in 60%, whereas Ski was immunodetected in the cytoplasm and nuclei in 44.5% and 17.6% of the cases, respectively. Smad-7 expression was positively correlated with tumor size, stage, matrix metalloproteinase (MMP)-9, and MMP-14. Cytoplasmic Ski expression was negatively associated with tumor size, stage, and lymph node status, and its nuclear expression was negatively related to histologic grade. Cytoplasmic Ski expression was associated with longer overall and disease-free survival. It appears that two negative regulators of the transforming growth factor-β pathway, Smad-7 and Ski, behave differentially in invasive breast carcinomas. Smad-7 appears to be related with an aggressive phenotype, whereas Ski expression is related to a less aggressive behavior and positively influences patients' survival.

The Dual Role of Smad7 in the Control of Cancer Growth and Metastasis

“…Theohari and colleagues investigated the expression of Smad7 in 150 invasive breast carcinoma specimens and showed that Smad7 levels positively correlate with tumor size, stage, matrix metalloproteinase (MMP)-9 and MMP-14 expression thus resulting in an aggressive phenotype [56]. However, experimental evidence suggests that Smad7 can regulate either positively or negatively breast carcinogenesis.…”

SND1 Acts Downstream of TGFβ1 and Upstream of Smurf1 to Promote Breast Cancer Metastasis

“…Western blot was done to detect the protein level of SND1, Smurf1, and RhoA. F, the total cell lysates of different treated MCF-7 cells (top) were immunoprecipitated with anti IgG (lanes 1-4) or anti-RhoA (lanes [5][6][7][8] antibody, then subjected to antiRhoA (top) or antiubiquitination (bottom) immunoblotting.…”

“…The misregulation of TGFb signaling may promote tumor invasion and migration, leading to detrimental consequences for prognosis in patients with breast cancer (3)(4)(5). The TGFb signaling pathway contains different R-Smads (Smad1, Smad2, Smad3, and Smad5) and co-Smad (Smad4) transcription factors (6)(7)(8). Smad1, Smad5, and Smad8 are specifically activated by the bone morphogenetic protein (BMP) receptors, whereas Smad2 and Smad3 are specifically activated by TGFb-related receptors (9).…”

Phospho-specific Smad3 signaling

“…66 In invasive breast cancer tissue samples, increased cytoplasmic SKI expression is inversely associated with tumor size, stage and lymph node status and positively associated with longer disease-free survival. 67 Research on the consequences of SKI action on Smad3 linker phosphorylation is actively being pursued in breast cancer cells.…”