Tamoxifen Resistant Breast Cancers: Inappropriate Transcriptional Coregulators

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 ORF93. In the first year we cloned the full-length cDNA assembled its genomic structure localized the gene to chromosome 15q26. 1 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 started and are ongoing. The protein does not appear to have a major effect on transcription anti sense studies have been devised to test this further. Significance. We now believe that ORF93 has a cytoplasmic scaffolding function, and allows receptors to interact with other proteins in multiprotein complexes, perhaps in association with hsp90. If so, ORF93 may be important for cross-talk between growth factor and nuclear receptor signaling pathways.