Role of Changes in the Expression of Cyclins and Retinoblastoma Protein in the Development of Breast Cancer.
Abstract
In the first three years of the grant, as described previously and in the present annual report, we have established a panel of 12 available breast cancer and normal breast epithelial cell lines, and characterized them with respect to the expression of a total of 13 cell cycle regulatory proteins by immunoblotting. We also examined 10 matched pairs of normal breast and breast tumor tissue for the expression of Rb (retinoblastoma) cyclin Dl and p16 (multiple tumor suppressor 1) proteins. These studies, along with studies from other laboratories, have indicated that one or more defects in the Rb-cyclin D1-p16 cell cycle regulatory system are present in a large majority of breast cancer cells. We have also investigated the mechanisms that lead to overexpression of cyclin Dl and the failure to express p16 in breast cancer. Cyclin Dl expression is associated with amplification of the cyclin Dl gene and increases in cyclin Dl mRNA expression as well as, in one case, an increase in the half-life of the cyclin Dl protein. In addition, expression of cyclin Dl protein in breast cancer cell lines is independent of growth factor regulation, and largely unaffected by cell-cell contact. Failure to express pl6 has been shown to be due to either homozygous deletion or methylation of the gene in 70 percent of breast cancer cell lines. We have now expressed pl6 protein under the control of the inducible Tet promoter in breast cancer cells lacking pl6 production, and will test the effect of restoration of pl6 expression on the tumorigenicity of these cells. We have also initiated a study of cyclin Dl, CDK4 and CDK6- associated kinase activity in breast cancer cells.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 1997
- Accession Number
- ADA337790
Entities
People
- Thomas A. Langan
Organizations
- University of Colorado Boulder