The uterine and vascular actions of estetrol delineate a distinctive profile of estrogen receptor α modulation, uncoupling nuclear and membrane activation

Anne Abot, Coralie Fontaine, Mélissa Buscato, Romain Solinhac, Gilles Flouriot, Aurélie Fabre, Anne Drougard, Shyamala Rajan, Muriel Laine, Alain Milon, Isabelle Muller, Daniel Henrion, Marine Adlanmerini, Marie Cécile Valéra, Anne Gompel, Céline Gerard, Christel Péqueux, Mélanie Mestdagt, Isabelle Raymond-Letron, Claude KnaufFrançois Ferriere, Philippe Valet, Pierre Gourdy, Benita S. Katzenellenbogen, John A. Katzenellenbogen, Françoise Lenfant, Geoffrey L. Greene, Jean Michel Foidart, Jean François Arnal

Research output: Contribution to journalArticle

Abstract

Estetrol (E4) is a natural estrogen with a long half-life produced only by the human fetal liver during pregnancy. The crystal structures of the estrogen receptor α (ERα) ligand-binding domain bound to 17β-estradiol (E2) and E4 are very similar, as well as their capacity to activate the two activation functions AF-1 and AF-2 and to recruit the coactivator SRC3. In vivo administration of high doses of E4 stimulated uterine gene expression, epithelial proliferation, and prevented atheroma, three recognized nuclear ERα actions. However, E4 failed to promote endothelial NO synthase activation and acceleration of endothelial healing, two processes clearly dependent on membrane-initiated steroid signaling (MISS). Furthermore, E4 antagonized E2 MISS-dependent effects in endothelium but also in MCF-7 breast cancer cell line. This profile of ERα activation by E4, uncoupling nuclear and membrane activation, characterizes E4 as a selective ER modulator which could have medical applications that should now be considered further.

Original languageEnglish (US)
Pages (from-to)1328-1346
Number of pages19
JournalEMBO Molecular Medicine
Volume6
Issue number10
DOIs
StatePublished - Oct 1 2014

Keywords

  • Endothelium
  • Estetrol
  • Estrogen receptor
  • Uterus

ASJC Scopus subject areas

  • Molecular Medicine

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    Abot, A., Fontaine, C., Buscato, M., Solinhac, R., Flouriot, G., Fabre, A., Drougard, A., Rajan, S., Laine, M., Milon, A., Muller, I., Henrion, D., Adlanmerini, M., Valéra, M. C., Gompel, A., Gerard, C., Péqueux, C., Mestdagt, M., Raymond-Letron, I., ... Arnal, J. F. (2014). The uterine and vascular actions of estetrol delineate a distinctive profile of estrogen receptor α modulation, uncoupling nuclear and membrane activation. EMBO Molecular Medicine, 6(10), 1328-1346. https://doi.org/10.15252/emmm.201404112