Transforming Growth Factor Beta (TGF-beta) is one of the most potent naturally occurring inhibitors of normal cell growth. TGF-beta exerts its action by binding to a type I (TbetaR-I) and a type II (TbetaR-II) transmembrane receptor located on the cell membrane. Downstream signaling is mediated by TbetaR-I once the ligand had bound both receptors. Three proteins, Smad2, Smad3 and Smad4/DPC4 have been found to be essential downstream components of the TGF-beta signaling pathway in mammalian cells. The growth inhibitory effects of TGF-beta on target cells include induction of G1 arrest, promotion of terminal differentiation or activation of cell death mechanisms. Losses in these signaling pathways may predispose to or cause cancer. This hypothesis was confirmed with the finding that TGF-beta type II (TbetaR-II) receptor is inactivated by mutations in gastrointestinal cancer with microsatellite instability. Targeting of the TGF-beta pathway in cancer is additionally demonstrated by the identification of inactivating mutations in Smad4/DPC4 in colon, breast, ovary, lung and head and neck cancer and Smad2 in colon cancer. Recent reports show that germline mutations of TbetaR-II and Smad4/DPC4 may predispose to the development of hereditary non-polyposis colorectal cancer and juvenile polyposis, respectively. My work has lead to the discovery of the first mutations of the type I TGF-beta receptor, a 9-bp deletion and 3-bp insertion coined TbetaR- I(6A) and TbetaR-I(10a), respectively. Current data suggest that the frequency of TbetaR-I(6A) heterozygotes is roughly similar in patients with cancer and in healthy blood donors of comparable ethnic status. However, there were seven TbetaR-I(6A) homozygotes and seven TbetaR- I(10A) heterozygotes among 211 patients with a diagnosis of cancer while there were none among 118 healthy donors of similar ethnic status. TbetaR-I(6A) homozygotes and TbetaR-I(10A) heterozygotes may therefore be at greater risk of developing cancer. Transient transfection of TbetaR-I(6A) into cells devoid of TbetaR-I restored TGF-beta signaling. However, it seems that subtle effects generated by the homozygous TbetaR-I(6A) phenotype are linked with cancer development. TbetaR-I(10A) TGF-beta signaling function is unknown. This application's objectives are to investigate in depth the biological significance of TbetaR-I(6A) and TbetaR-I(10A).

K08CA076156

1999-07-01

2002-06-30