Role of Nuclear Receptor Coregulators in Hormone Resistant Breast Cancer

摘要

We propose that coregulatory proteins influence the direction of transcription by antagonist-occupied steroid receptors. We screened for such proteins and identified three cDNA fragments encoding peptides that interact with antagonist-bound PRs. The aims were to clone complete cDNAs; define the role of the unknown proteins on receptor activity; and determine the role of the unknown proteins in hormone dependency of breast cancers. Major findings: We have focused on one novel cDNA fragment, designated ORF number 93. We cloned the full- length cDNA; localized the gene to chromosome l5q23.l; expressed the full-length protein; defined its tissue distribution; and determined that it is cytoplasmic. ORF number 93 doesn't appear to have a ligand-specific effect on PR transcription, but it does have general transcriptional effects. Prom mammalian two-hybrid and GST pull-down assays, we've determined that ORF number 93 interacts with hsp9O and that this is influenced by the presence of PR and its ligands. It's possible that ORF number 93 functions to regulate key events in the formation of nascent PR, cytoplasmic chaperone interactions and translocation into the nucleus. If so, ORF number 93 may play a key role in bringing PR to associate with cytoplasmic molecules with which PR would otherwise not interact.