Defective transforming growth factor beta signaling pathway in head and neck squamous cell carcinoma as evidenced by the lack of expression of activated Smad2

Purpose: Transforming growth factor beta (TGF-beta) regulates cell growth a nd differentiation, in normal squamous epithelium, via specific TGF-beta re ceptors and intracellular signaling molecules (Smads), We have previously o bserved that TGF-beta type II receptor (T betaR-II) expression decreases in squamous cell carcinomas as tumors become less differentiated and more bio logically aggressive. However, a small fraction of tumors remain T betaR-II positive. Tn this article, we examine the integrity of the other members o f the TGF-beta -signaling machinery, the Smad proteins, Experimental Design: Thirteen archived head and neck squamous cell carcinom as were selected from the files of the Pathology Department of the H. Lee M offitt Cancer Center, Protein immunoexpression was quantitated by image ana lysis in the context of histopathological parameters. Mutation analysis of the MADR2/Smad2 gene was also performed, Results: In both T betaR-II-positive and TPR-II-negative tumors, expression of the non-TGF-beta -specific Smads (4, 6, and 7) was variable, whereas ex pression of the pathway-specific Smad2 was lost in 38% of the tumors. Expre ssion of the activated, phosphorylated form of this molecule, Smad2-P, was lost in approximately 70% of the tumors. No abnormal mRNA expression and no mutations in the MADR2/Smad2 gene were observed, Conclusions: These results suggest that multiple defects in TGF-beta signal ing, both at the receptor and postreceptor level, may play a role in the on cogenesis of head and neck squamous cell carcinoma.