Role of Nuclear Receptor Coregulators in Hormone Resistant Breast Cancer
Abstract
Development of resistance to the widely used antiestrogen, tamoxifen, is a prevalent issue in breast cancer patients. The mechanisms underlying tamoxifen resistance are poorly understood and occur despite continued estrogen receptor (ER) expression. Purpose: To determine whether the expression levels of transcriptional coregulators, which influence ER activity, affect tamoxifen sensitivity. Scope: I hypothesized that decreased levels of the corepressors SMRT and N-CoR, or an increase in levels of the coactivators, SRC- 1 and L7/SPA, in breast tumors, results in an increase in the partial agonist activity of tamoxifen, expressed as "resistance". Major Findings: I developed and optimized a sensitive and quantitative assay to measure coregulator expression levels in breast cancer cell lines and tumors. Using the assay, expression levels of the four coregulators were measured in a group of tamoxifen sensitive and resistant tumors. N-CoR and SMRT levels were overall lower in tamoxifen resistant tumors, compared with the tamoxifen sensitive group. The levels of coactivator expression did not differ among the tumors. Furthermore, ER transcriptional studies in the presence of SMRT suggest that coregulators suppress the partial agonist activity of tamoxifen by a novel mechanism. Significance: Statistical analysis of my results suggests that decreased levels of corepressor expression in breast tumors may predict the development of tamoxifen resistance. The coactivators SRC-1 and L7/SPA may not be involved in tamoxifen resistance. On the other hand, other coactivators that are yet to be defined may play a role in the increased partial agonist activities of mixed antagonists, and the transition to a resistant phenotype.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2000
- Accession Number
- ADA385320
Entities
People
- Justine D. Graham
- Kathryn B. Horwitz
Organizations
- University of Colorado Health