Estrogen and Retinoid Regulation of DNA Repair in Breast Cancer
Abstract
Chemotherapeutic agents used in the treatment breast cancer produce their cytotoxic effects by creating DNA damage. Estrogen (ER) and retinoic acid receptors (RAR) are members of a family of ligand dependent transcription factors. ER, RAR, and BRCAl require CREB binding protein (CBP) to activate target gene transcription. The application proposed a new mechanism by which ER and RAR regulate BRCAl mediated DNA repair via CBP. In the second year of the project, we determined that RARalpha overexpression in ER negative breast cancer cell lines enhances the deleterious effects of RA on DNA damage induced apoptosis. Treatment with the DNA methyltransferase inhibitor ADC failed to induce additional BRCAl expression in BR negative breast cancer cell lines. A novel BRCAl mutant protein repressed expression of a number of double strand break repair proteins in the Rad and XRCC groups. However, both T47D and MDA-MBA68 clones expressing the novel BRCAl mutant protein were more resistant to the effects of etoposide treatment These results may be due to the pronounced cell cycle inhibitory effect of the BRCAl mutant protein, thereby rendering the slower dividing cells less sensitive to the topoisomerase inhibitor.
Document Details
- Document Type
- Technical Report
- Publication Date
- May 01, 2004
- Accession Number
- ADA425727
Entities
People
- David L Crowe
Organizations
- University of Southern California