Definition of the Cellular Mechanisms Which Distinguish Between Estrogen Receptor Agonists and Antagonists
Abstract
Estrogen is a mitogen in most estrogen receptor (ER) positive breast cancers and anti-estrogens like tamoxifen have been the mainline therapies for these types of cancers. 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 interacting coactivators required for its transcriptional activity. We have successfully probed the ER:coactivator interaction surfaces using peptides isolated from combinatorial phage display libraries. Several different classes of peptides were identified that recognized specific ligand-bound ER conformations. Using these peptides we were able to determine at least two functionally important protein-protein interaction surfaces on ER. One surface is exposed when the receptor is activated by pure agonists and the other surface is formed only when the receptor is bound by tamoxifen. We found a number of peptides that recognize the agonist-induced conformation which can block estradiol-induced ER transcriptional activity. Additionally, we also identified peptides that recognize tamoxifen-bound ER which can antagonize tamoxifen partial agonist activity when expressed in target cells. Both of these classes of peptides have potential to be developed into peptide antagonists for the treatment of breast cancers.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2000
- Accession Number
- ADA388867
Entities
People
- Ching-Yi Chang
- Donald P McDonnell
Organizations
- Duke University Hospital