Mutation of the TGF-beta type II receptor gene and the development of resistance to TGF-beta represent relatively late events in the process of carcinogenesis and may make a key contribution to the transition from late adenoma to frank malignancy. Previously, we reported a correlation between resistance to TGF-beta in human gastric cancer cell lines and gross structural abnormalities of the TGF-beta type II receptor gene. We have also established a correlation between microsatellite instability and TGF-beta RII gene mutations in human gastric carcinoma. A screen of the gastric cancer cell lines included in our previous study has detected microsatellite instability in two cell lines, SNU-1 and -638. Both cell lines are resistant to TGF-beta and demonstrate undetectable levels of TGF-beta RII transcripts. Similarly, we have screened genomic DNAs from several other types of malignancy for the presence of microsatellite instability. Despite the occurrence of defective DNA repair in these other tumor types (osteosarcoma, ovarian cancer and hepatocellular carcinoma), TGF-beta-RII mutations were not identified. This result suggests that association between defective DNA mismatch repair and mutation of TGF-beta RII may be a feature of only selected carcinogenic pathways which include those for colon and gastric cancer and that the relationship is not a general phenomenon shared by all types of malignancy. In many cases, resistance to TGF-beta in human cancer cells cannot be explained by receptor system defects. We have studied several TGF-beta resistant cell lines which fail to express TGF-beta type II receptor protein, but have no identifiable mutation in the TGF-beta RII structural gene. In several cases, Northern analysis demonstrated low or undetectable levels of TGF-beta RII mRNA, introducing the possibility that abnormalities of TGF-beta RII transcriptional regulation may also contribute to the development of resistance to TGF- beta in cancer. We have cloned and characterized the TGF-beta RII promoter. The promoter region contains two positive regulatory elements and two negative regulatory elements in addition to the core promoter element. Preliminary evidence suggests that cancer cells might display differences in transcription factors which bind to regulatory elements in the TGF-beta RII promoter.
