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

  • EMBO Mol Med. 2014 Oct;6(10):1328-46. doi: 10.15252/emmm.201404112.
Anne Abot  1 ,  Coralie Fontaine  1 ,  Mélissa Buscato  1 ,  Romain Solinhac  1 ,  Gilles Flouriot  2 ,  Aurélie Fabre  1 ,  Anne Drougard  1 ,  Shyamala Rajan  3 ,  Muriel Laine  3 ,  Alain Milon  4 ,  Isabelle Muller  4 ,  Daniel Henrion  5 ,  Marine Adlanmerini  1 ,  Marie-Cécile Valéra  1 ,  Anne Gompel  6 ,  Céline Gerard  7 ,  Christel Péqueux  7 ,  Mélanie Mestdagt  7 ,  Isabelle Raymond-Letron  8 ,  Claude Knauf  1 ,  François Ferriere  2 ,  Philippe Valet  1 ,  Pierre Gourdy  1 ,  Benita S Katzenellenbogen  9 ,  John A Katzenellenbogen  9 ,  Françoise Lenfant  1 ,  Geoffrey L Greene  3 ,  Jean-Michel Foidart  7 ,  Jean-François Arnal  10
Affiliations
  • 1. INSERM U1048, Institut des Maladies Métaboliques et Cardiovasculaires, Université de Toulouse - UPS, Toulouse, France.
  • 2. Institut de Recherche en Santé Environnement et Travail, IRSET, INSERM U1085, Team TREC, Biosit, Université de Rennes I, Rennes, France.
  • 3. Department for Cancer Research, University of Chicago, Chicago, IL, USA.
  • 4. CNRS and Université de Toulouse, IPBS, Toulouse, France.
  • 5. INSERM U1083, CNRS UMR 6214, Université d'Angers, Angers, France.
  • 6. APHP, Unité de Gynécologie Endocrinienne, Université Paris Descartes, Paris, France.
  • 7. Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA-cancer), Université de Liège, Liège, Belgique.
  • 8. INP, ENVT, Université de Toulouse, Toulouse, France.
  • 9. Departments of Molecular and Integrative Biology and Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
  • 10. INSERM U1048, Institut des Maladies Métaboliques et Cardiovasculaires, Université de Toulouse - UPS, Toulouse, France [email protected].
PMID: 25214462 DOI: 10.15252/emmm.201404112
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.

Keywords
endothelium; estetrol; estrogen receptor; uterus.
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