Transforming Growth Factor-B Receptors in Humans
Final rept. 1 May 1996-31 Dec 2000
YALE UNIV NEW HAVEN CT
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Transforming Growth Factor-Beta TGF-Beta is the most potent known inhibitor of cell cycle progression of normal mammary epithelial cells. In general, advanced breast cancers are refractory to TGF-Beta-mediated growth inhibition. The TGF-Beta type I and type II receptors T-Beta-R-I and -II are the primary transducers of TGF-Betas antiproliferative effects. It is our working hypothesis that TGF-Beta-resistance is caused by lesions in the T-Beta-R genes. Using touch preps of primary breast carcinomas, we showed that approximately 50 of primary breast carcinomas contain subpopulations of cells that have lost one or both copies of the T-Beta-R-I or -II gene. Screening of the T-Beta-R-I and -II genes for the presence of mutations using PCR-SSCP and DNA sequencing indicate that a particular missense mutation S387Y in T-Beta-R-I is present in approximately 6 of primary cancers and 42 of axillary lymph node metastases. Finally, we have generated antibodies that specifically recognize the activated phosphorylated forms of Smad2 and -3. These allow us to assess in situ whether breast cancer cells are responding to TGF-Beta, and whether T-Beta-R defects are present or not. Approximately 12 of primary breast cancers fail to activate Smad2, indicating the presence of a TGF-Beta receptor defect.
- Genetic Engineering and Molecular Biology
- Medicine and Medical Research