Tamoxifen Resistant Breast Cancers: Inappropriate Transcriptional Coregulators
Abstract
The antiestrogen, tamoxifen, is currently the most effective hormonal agent for the treatment of breast cancer. The presence of nuclear estrogen (ER) and progesterone (PR) receptors in tumors is a strong prognostic marker for tamoxifen responsiveness. However, most tumors that initially regress, eventually become tamoxifen "resistant" and resume growing. Resistant tumors usually retain their ER. Tamoxifen is a mixed agonist/antagonist, a property that it shares with the antiprogestin RU486. Under certain conditions, mixed antagonists can impart strong, agonist-like, transcriptional activity. We postulated that in tamoxifen-resistant breast cancers, tamoxifen acquires strong agonist-like properties which override its antagonist effects. As a result, tamoxifen acts like an estrogen and enhances tumor growth. Our hypothesis as to the mechanism of hormone resistance involves the inappropriate recruitment of coregulatory proteins to the transcriptional machinery that switches the affect of antagonist hormones on their respective receptors. To define the molecular events that cause such a switch we used an antagonist-driven yeast two-hybrid screening strategy and isolated three antagonist-specific, receptor-interacting peptides. Our long-term goal is to understand how tamoxifen resistance develops, with a view to either preventing or reversing it.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2001
- Accession Number
- ADA403705
Entities
People
- Kathryn B. Horwitz
Organizations
- University of Colorado Health