Transforming Growth Factor-B Receptors in Human Breast Cancer
Abstract
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 TGFBeta's 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.
Document Details
- Document Type
- Technical Report
- Publication Date
- May 01, 2000
- Accession Number
- ADA383938
Entities
People
- Michael Reiss
Organizations
- Yale University