Transforming Growth Factor-B Receptors in Human Breast Cancer
Annual rept. 15 May 1996-30 Apr 2000
YALE UNIV NEW HAVEN CT
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Transforming Growth Factor-Beta TGFBeta is the most potent known inhibitor of cell cycle progression of normal mammary epithelial cells. In general, advanced breast cancers are refractory to TGFBeta-mediated growth inhibition. The TGFBeta type I and type II receptors TBetaR-l and -11 are the primary transducers of TGFBetas antiproliferative effects. It is our working hypothesis that TGFBeta-resistance is caused by lesions in the TBetaR 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 TBetaR-l or -Il gene. Screening of the TBetaR-l and -Il genes for the presence of mutations using PCR-SSCP and DNA sequencing indicate that a particular missense mutation S387Y in TBetaR-l 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 Smed2 and -3. These allow us to assess in situ whether breast cancer cells are responding to TGFBeta, and whether TBetaR defects are present or not. Approximately 12 of primary breast cancers fail to activate Smad2, indicating the presence of a TGFBeta receptor defect.
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