Role of Nuclear Receptor Coregulators in Hormone Resistant Breast Cancer
Abstract
To determine whether the agonist activities of tamoxifen are exaggerated in hormone-resistant breast cancers. Scope. We proposed that coregulatory proteins influence the direction of transcription by antagonist-occupied steroid receptors. We screened for such proteins, and identified three novel cDNA fragments encoding peptides that interact with antagonist-bound PRs. The aims were to clone the complete cDNAs and define their structure (Aim 1); define the role of the unknown proteins on receptor activity (Aim 2); and, if appropriate, determine the role of these proteins in hormone dependency of breast cancers (Aim 3). Major Findings - Results. We have focused on one novel cDNA fragment, designated ORF#g3. We cloned the full-length cDNA; assembled its genomic structure; localized the gene to chromosome I 5q23. I; expressed the full-length protein; defined its tissue distribution; determined its subcellular localization to be cytoplasmic; and generated a polyclonal antibody that probes a 103 kDa protein. Functional studies have been completed. The protein is not a ligand-specific transcriptional regulator, but does affect overall transcription. Antisense studies show ORF#93 also blocks corepressor action on ER. The protein does not affect PR nuclear translocation, but interacts also with hsp9O; Significance. We now believe that ORF#93 has a cytoplasmic "scaffolding" function, and allows receptors to interact with other proteins in multiprotein complexes, perhaps in association with hsp9O. If so, ORF#93 may be important for cross-talk between growth factor and nuclear receptor signaling pathways.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2001
- Accession Number
- ADA403446
Entities
People
- Justine D. Graham
Organizations
- University of Colorado Health