Accession Number : ADA446696


Title :   The Role of Estrogen Related Receptor in Modulating Estrogen Receptor Mediated Transcription in Breast Cancer Cells


Descriptive Note : Annual summary rept. 28 Mar 2003-27 Mar 2005


Corporate Author : DUKE UNIV DURHAM NC


Personal Author(s) : Gaillard, Stephanie ; McDonnell, Donald P


Full Text : https://apps.dtic.mil/dtic/tr/fulltext/u2/a446696.pdf


Report Date : Apr 2005


Pagination or Media Count : 20


Abstract : Unlike most nuclear receptors, the Estrogen Receptor-Related Receptors (ERRs) activate transcription constitutively, interacting with coactivators and target gene promoters in the absence of ligand. Structurally, this subfamily of receptors is related to the classical estrogen receptors and has been shown to positively regulate the transcription of several estrogen responsive genes. Interestingly, the transcriptional activity of ERRalpha is not inhibited by classical anti-estrogens suggesting that its ability to regulate ER- responsive genes may contribute to the development of tamoxifen resistant breast cancer. Without pharmacological agents to regulate ERRalpha activity it has been difficult to define the specific roles of this orphan receptor in the pathogenesis of breast cancer and thus its potential as a therapeutic target is unknown. To address this issue we have developed approaches to both positively and negatively regulate ERRalpha activity in target cells. Specifically, we have developed peptide antagonists to inhibit ERRalpha activity by blocking cofactor binding and have developed activating protein ligands by creating modified coactivators that selectively regulate ERRalpha transcriptional activity. With these tools, we have characterized the critical regions of the receptor important for coactivator binding and defined differential binding requirements between coactivator families. In addition, we are identifying the target genes and processes regulated by ERRalpha.


Descriptors :   *RECEPTOR SITES(PHYSIOLOGY) , *PHARMACOLOGICAL ANTAGONISTS , *ESTROGENS , *TRANSCRIPTION(GENETICS) , *BREAST CANCER , REQUIREMENTS , ACTIVATION , PEPTIDES , RESISTANCE , PROTEINS , TARGETS , LIGANDS , THERAPY , GENES , DRUGS , MODULATION , CELLS(BIOLOGY) , PATHOGENESIS , SENSE ORGANS


Subject Categories : Anatomy and Physiology
      Medicine and Medical Research
      Pharmacology


Distribution Statement : APPROVED FOR PUBLIC RELEASE