Transforming Growth Factor-B Receptors in Humans

摘要

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-Beta's 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.