Specific mutations in the estrogen receptor change the properties of antiestrogens to full agonists

摘要: The estrogen receptor (ER) stimulates transcription of target genes by means its two transcriptional activation domains, AF-1 in the N-terminal part and AF-2 ligand-binding domain. activity is dependent upon a putative amphipathic alpha-helix between residues 538 552 mouse ER. Point mutagenesis conserved hydrophobic within this region reduces estrogen-dependent without affecting hormone DNA binding significantly. Here we show that these mutations dramatically alter pharmacology antagonists. Both tamoxifen ICI 164,384 behave as strong agonists HeLa cells expressing ER mutants. In contrast to wild-type ER, mutant receptors maintain nuclear localization DNA-binding after treatment. Structural alterations caused gene such those described herein or estrogen-independent signaling pathways may account for insensitivity some breast cancers