Definition of the Cellular Mechanisms Which Distinguish Between Estrogen Receptor Agonists and Antagonists
Abstract
Estrogen is mitogenic in most estrogen receptor (ER) positive breast cancers and the use of anti-estrogen like tamoxifen has been quite successful in the treatment of this disease. Although patients initially respond well to anti-estrogens, resistant tumors often develop within 5-10 years of treatment. The purpose of this research is to develop mechanistically distinct therapeutics by directly blocking the interaction of ER with coactivator proteins required for its activity. We have identified conformation-sensing peptide probes that detect different estrogen receptor conformations, and which when introduced into cells abolish ER transcriptional activity in transient transfection assays. These same peptides however do not seem to have an effect on endogenous ER activity. Studies are underway to investigate this discrepancy. Since the androgen receptor (AR) is highly expressed in most breast cancers, it is recognized now that AR may also play a role in the progression of these cancers. We therefore extended our studies to include the investigation of the mechanisms underlying androgen receptor (AR) mediated transcription, using peptides that we identified in the primary ER screen. We found that the ligand binding domain of AR has a unique structure which prohibits its interaction with the p160 coactivators, and that it recruits coactivator protein in a manner which is distinct from other nuclear receptors. It is anticipated that exploitation of the complexities of ER and AR action will lead to the development of novel breast cancer therapeutics.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2002
- Accession Number
- ADB284965
Entities
People
- Ching-Yi Chang
- Donald P McDonnell
Organizations
- Duke University Hospital