Peptide antagonists of the human estrogen receptor.
Estrogen receptor alpha transcriptional activity is regulated by distinct conformational states that are the result of ligand binding. Phage display was used to identify peptides that interact specifically with either estradiol- or tamoxifen-activated estrogen receptor alpha. When these peptides were coexpressed with estrogen receptor alpha in cells, they functioned as ligand-specific antagonists, indicating that estradiol-agonist and tamoxifen-partial agonist activities do not occur by the same mechanism. The ability to regulate estrogen receptor alpha transcriptional activity by targeting sites outside of the ligand-binding pocket has implications for the development of estrogen receptor alpha antagonists for the treatment of tamoxifen-refractory breast cancers.
Norris
J D
JD
Duke University Medical Center, Department of Pharmacology and Cancer Biology, Durham, NC 27710, USA.
Paige
L A
LA
Christensen
D J
DJ
Chang
C Y
CY
Huacani
M R
MR
Fan
D
D
Hamilton
P T
PT
Fowlkes
D M
DM
McDonnell
D P
DP
D000595:Amino Acid Sequence; D001665:Binding Sites; D004958:Estradiol / Q000378:metabolism / Q000494:pharmacology*; D004965:Estrogen Antagonists / Q000494:pharmacology*; D047628:Estrogen Receptor alpha; D006801:Humans; D008024:Ligands; D015735:Mifepristone / Q000494:pharmacology; D008969:Molecular Sequence Data; D019151:Peptide Library; D010455:Peptides / Q000378:metabolism / Q000494:pharmacology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D011960:Receptors, Estrogen / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D013629:Tamoxifen / Q000378:metabolism / Q000494:pharmacology*; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects
D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D008024:Ligands; D019151:Peptide Library; D010455:Peptides; D018160:Receptors, Cytoplasmic and Nuclear; D011960:Receptors, Estrogen; D011993:Recombinant Fusion Proteins; D018808:Transcription Factor AP-1; D013629:Tamoxifen; D015735:Mifepristone; D004958:Estradiol