Transforming Growth Factor-B Receptors in Human Breast Cancer
Abstract
Transforming Growth Factor-B (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 -II receptors (TBetaR-I and -II) are the primary transducer of TGFBeta's growth inhibitory effect. It is our working hypothesis that TGFBeta-resistance is caused by molecular lesions in the TBetaR genes. We first asked whether or not molecular lesions of the TGFBeta receptor genes are involved in the origin and/or progression of breast cancer. Our findings indicate that a specific somatic mutation within the kinase domain of the TBetaR-I receptor (S387Y) occurs in primary breast cancers, and, more commonly, in lymph node metastases. This is the first example of a missense mutation in this gene in human malignancy. Secondly, we demonstrated that the S387Y mutation has a negative impact on the ability of the TBetaR-I receptor to transduce the TGFBeta signal. Finally, we have shown that allelic losses of both the TBetaR-I and -II genes occur in subpopulations of cells contained within primary breast carcinomas, suggesting that TGFBeta-refractory clones are selected for during breast cancer progression.
Document Details
- Document Type
- Technical Report
- Publication Date
- May 01, 1999
- Accession Number
- ADA371248
Entities
People
- Michael Reiss
Organizations
- Yale University