Expression and clinical significance of the transforming growth factor-ß signalling pathway in endometrial cancer.

ABSTRACT

AIMS: To evaluate the components of the transforming growth factor (TGF)-ß-Smad signalling pathway in human endometrial cancer (EC). METHODS AND RESULTS: TGF-ß1, TGF-ß receptor type I, TGF-ß receptor type II, Smad2, Smad3, Smad4, Skil and Disabled-2 (DAB2) mRNA levels were determined by reverse transcriptase polymerase chain reaction on EC cell lines and in 70 EC tissues. Immunohistochemistry for Skil and DAB2 antibodies was performed on 362 EC cases. Decreased mRNA levels of all eight components of the TGF-ß pathway tested were found in the majority of 70 cases. For DAB2, the mRNA level was correlated with protein expression level (P = 0.04). The Skil mRNA level was associated with tumour stage (P = 0.03), and the Smad2/3/4 mRNA level with tumour grade (P = 0.03, P = 0.02, and P = 0.00, respectively). The Smad4 mRNA level was also associated with tumour size (P = 0.05), subtype (P = 0.04), and disease-free survival (DFS) (P = 0.05). The TGF-ß1 mRNA level was associated with DFS (P = 0.04). Finally, tumours with positive Skil protein expression had a shorter recurrence time, whereas, those with positive DAB2 protein expression had a longer recurrence time. CONCLUSIONS: Down-regulation of the TGF-ß-Smad signalling pathway might be responsible for the pathogenesis of human EC, and some of its components appeared to be prognostic factors. Exploration of future therapy targeting the TGF-ß-Smad pathway is warranted in EC.