The Role of Estrogen Related Receptor in Modulating Estrogen Receptor Mediated Transcription in Breast Cancer Cells
Abstract
Estrogen-related receptors (ERRs) are orphan members of the nuclear receptor super family of ligand-dependent transcription factors. Unlike estrogen receptors (ERs), ERRs are unresponsive to natural estrogens and activate transcription constitutively, interacting with required coactivators and DNA-binding elements in the absence of ligand. ERR-alpha has been shown to 1) activate the transcription of pS2, a breast cancer marker; 2) be unresponsive to hormonal therapies, i.e. Tamoxifen; and 3) correlate with unfavorable prognosis in breast tumors. Thus ERR-alpha could be a predictive marker of breast tumor hormone responsiveness and may be a suitable therapeutic target for hormone resistant breast cancers. Therefore, understanding the convergence of the ER and ERR signaling pathways is critical to clarifying the role of ERRs in modulating hormone response. Without specific ligands to modulate ERRs, studies of the physiological contributions of these receptors has been limited. We proposed to develop peptide antagonists to specifically inhibit the transcriptional activity of ERRs by blocking receptor-cofactor interactions. Peptides were identified by phage display screening that are capable of inhibiting ERR-mediated transcription without disrupting the transcriptional activity of other nuclear receptors, e.g. ER-alpha and ER-beta, validating the use of these peptides as specific ERR antagonists. In addition, using these peptides we have identified key regulatory surfaces on the ERR protein that permit the interaction of the receptor with previously validated ERR-coactivators.
Document Details
- Document Type
- Technical Report
- Publication Date
- Apr 01, 2004
- Accession Number
- ADA424198
Entities
People
- Donald P McDonnell
- Stephanie Gaillard
Organizations
- Duke University