Differential SERM activation of the estrogen receptors (ERalpha and ERbeta) at AP-1 sites.
BACKGROUND
The selective estrogen receptor modulators (SERMs) raloxifene and tamoxifen are triphenylethylene derivatives that affect transcriptional regulation by the estrogen receptors (ERalpha and ERbeta) but show different effects in different tissues. A third triphenylethylene derivative, GW-5638, displays tissue selectivity in rats identical to that of raloxifene, suggesting that GW-5638 and raloxifene share a mechanism of action that is different from that of tamoxifen.


RESULTS
Both GW-5638 and its hydroxylated analog GW-7604 were tested for their ability to bind to ERalpha and ERbeta and their ability to affect transcription of ERalpha and ERbeta at a consensus estrogen response element and an ER/AP-1 response element. The drugs were found to have the same affinity for ERalpha and ERbeta, although they were also found to activate transcription from an AP-1 promoter element more potently with ERbeta than with ERalpha. Derivatives of GW-5638 with alterations at the carboxylic acid still showed increased ERbeta potency compared to ERalpha, but the magnitude of the activation with ERalpha was much higher than with ERbeta.


CONCLUSIONS
Despite similar binding affinities to isolated ERalpha and ERbeta, GW-5638 and GW-7604 show markedly lower EC(50) values with ERbeta at an AP-1-driven promoter as compared to ERalpha. This suggests that the two compounds produce a more active ER/AP-1 conformation of the ER/AP-1 transcription factor complex when bound to ERbeta than when bound to ERalpha.
Weatherman
R V
RV
Departments of Pharmaceutical Chemistry and Cellular and Molecular Pharmacology, University of California, San Francisco 94143-0446, USA.
Clegg
N J
NJ
Scanlan
T S
TS
D002934:Cinnamates / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D005260:Female; D005809:Genes, Regulator / Q000187:drug effects / Q000235:genetics; D006367:HeLa Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D011485:Protein Binding / Q000502:physiology; D020849:Raloxifene Hydrochloride / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011960:Receptors, Estrogen / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D020845:Selective Estrogen Receptor Modulators / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D013267:Stilbenes / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D013629:Tamoxifen / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects* / Q000235:genetics
D002934:Cinnamates; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D011960:Receptors, Estrogen; D020845:Selective Estrogen Receptor Modulators; D013267:Stilbenes; D018808:Transcription Factor AP-1; D013629:Tamoxifen; C087550:3-(4-(1,2-diphenylbut-1-enyl)phenyl)acrylic acid; D020849:Raloxifene Hydrochloride; C037749:triphenylethylene