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Research ArticlePERSPECTIVES IN PHARMACOLOGY

Molecular Mechanisms of Selective Estrogen Receptor Modulator (SERM) Action

Martin Dutertre and Carolyn L. Smith
Journal of Pharmacology and Experimental Therapeutics November 2000, 295 (2) 431-437;
Martin Dutertre
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Carolyn L. Smith
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Abstract

In females, estrogens play a key role in reproduction and have beneficial effects on the skeletal, cardiovascular, and central nervous systems. Most estrogenic responses are mediated by estrogen receptors (ERs), either ERα or ERβ, which are members of the nuclear receptor superfamily of ligand-dependent transcription factors. Selective estrogen receptor modulators (SERMs) are ER ligands that in some tissues act like estrogens, but block estrogen action in others. Thus, SERMs may exhibit an agonistic or antagonistic biocharacter depending on the context in which their activity is examined. For example, the SERMs tamoxifen and raloxifene both exhibit ER antagonist activity in breast and agonist activity in bone, but only tamoxifen manifests agonist activity in the uterus. Numerous studies have examined the molecular basis for SERM selectivity. Collectively they indicate that different ER ligands induce distinct structural changes in the receptor that influence its ability to interact with other proteins (e.g., coactivators or corepressors) critical for the regulation of target gene transcription. The relative expression of coactivators and corepressors, and the nature of the ER and of its target gene promoter affect SERM biocharacter. Taken together, SERM selectivity reflects the diversity of ER forms and coregulators, cell type differences in their expression, and the diversity of ER target genes. This model provides a basis for understanding the molecular mechanisms of SERM action, and should help identify new SERMs with enhanced tissue or target gene selectivity.

Footnotes

  • Send reprint requests to: Carolyn L. Smith, Ph.D., Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030. E-mail:carolyns{at}bcm.tmc.edu

  • ↵1 This work was supported by National Institutes of Health Grant DK53002.

  • Abbreviations:
    SERM
    selective estrogen receptor modulator
    AF
    activation function
    AP-1
    activator protein-1
    CBP
    cyclic AMP response element binding protein-binding protein
    C/EBPβ
    CCAAT/enhancer-binding protein β
    DBD
    DNA binding domain
    ER
    estrogen receptor
    ERE
    estrogen response element
    HET/SAF-B
    Hsp27 ERE-TATA binding protein/scaffold attachment factor B
    L7/SPA
    L7/switch protein for antagonists
    LBD
    ligand binding domain
    N-CoR
    nuclear receptor corepressor
    NF-κB
    nuclear factor-κB
    REA
    repressor of estrogen receptor activity
    SMRT
    silencing mediator of retinoic acid and thyroid hormone receptors
    SRC
    steroid receptor coactivator
    • Received April 14, 2000.
    • Accepted July 13, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 295 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 295, Issue 2
1 Nov 2000
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Research ArticlePERSPECTIVES IN PHARMACOLOGY

Molecular Mechanisms of Selective Estrogen Receptor Modulator (SERM) Action

Martin Dutertre and Carolyn L. Smith
Journal of Pharmacology and Experimental Therapeutics November 1, 2000, 295 (2) 431-437;

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Research ArticlePERSPECTIVES IN PHARMACOLOGY

Molecular Mechanisms of Selective Estrogen Receptor Modulator (SERM) Action

Martin Dutertre and Carolyn L. Smith
Journal of Pharmacology and Experimental Therapeutics November 1, 2000, 295 (2) 431-437;
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