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The transforming growth factor-betas (TGF-βs) are multifunctional proteins that inhibit the proliferation of many epithelial cells through a set of cell protein receptors that includes the TGF-β type I (RI) and type II (RII) receptors. Loss of growth inhibition by TGF-β is thought to contribute to the development of many types of tumors. In the present study, we have examined expression of the proteins and mRNAs for TGF-β1 , TGF-β RI, and TGF-β RII in normal human lung, well-characterized non-small cell lung cancer (NSCLC) cell lines, and primary NSCLC specimens. Immunohistochemical staining for TGF-β 1 , TGF-β RI, and TGF-β RII using specific antibodies in normal human lung showed expression of the 3 proteins in the epithelium of bronchi and bronchioles as well as in alveoli. Differential expression of TGF-β RI and TGF-β RII proteins was detected in 5 NSCLC cell lines using Western blot analysis, with reduced levels in 3 cell lines. A panel of 45 formalin-fixed and paraffin-embedded NSCLC specimens showed positive immunostaining for TGF-β 1 , TGF-β RI, and TGF-β RII, with reduced TGF-β RII in poorly differentiated adenocarcinomas and squamous cell carcinomas and some moderately differentiated adenocarcinomas. In situ hybridization studies conducted with specific riboprobes for TGF-β 1 , TGF-β RI, and TGF-β RII showed corresponding localization of expression of the mRNAs in the specimens that showed positive immunostaining for the proteins. To investigate the roles of TGF-β 1 , TGF-β RI, and TGF-β RII in chemically induced mouse lung tumorigenesis, we examined the expression of their proteins and mRNAs in 2 mouse model systems. Whereas expression of the proteins and mRNAs for TGF-β 1 and TGF-β RI was comparable in lung adenomas and bronchioles of A/Jmice treated with benzo(α)pyrene, decreased immunostaining and hybridization for TGF-β RII protein and mRNA was detected in 50% of lung adenomas in these mice. Interestingly, expression of TGF-β 1 and the TGF-β receptor proteins was similar to that of bronchioles in C57B1/6mice and their littermates heterozygous for deletion of the TGF-β 1 gene treated with diethylnitrosamine. These data show that reduced levels of expression of TGF-β RII occur in some, but not all, human and mouse lung tumors. This suggests that different mechanisms of action, some of which may involve the TGF-β signaling pathway, may contribute to the progression of lung tumorigenesis. [ABSTRACT FROM AUTHOR]