Purpose: Transforming growth factor β (TGF-β) regulates cell growth and differentiation, in normal squamous epithelium, via specific TGF-β receptors and intracellular signaling molecules (Smads). We have previously observed that TGF-β type II receptor (TβR-II) expression decreases in squamous cell carcinomas as tumors become less differentiated and more biologically aggressive. However, a small fraction of tumors remain TβR-II positive. In this article, we examine the integrity of the other members of the TGF-β-signaling machinery, the Smad proteins.

Experimental Design: Thirteen archived head and neck squamous cell carcinomas were selected from the files of the Pathology Department of the H. Lee Moffitt Cancer Center. Protein immunoexpression was quantitated by image analysis in the context of histopathological parameters. Mutation analysis of the MADR2/Smad2 gene was also performed.

Results: In both TβR-II-positive and TβR-II-negative tumors, expression of the non-TGF-β-specific Smads (4, 6, and 7) was variable, whereas expression of the pathway-specific Smad2 was lost in 38% of the tumors. Expression 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-β signaling, both at the receptor and postreceptor level, may play a role in the oncogenesis of head and neck squamous cell carcinoma.