title: The uterine and vascular actions of estetrol delineate a distinctive profile of estrogen receptor α modulation, uncoupling nuclear and membrane activation.
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.
authors.affiliation: INSERM U1048, Institut des Maladies Métaboliques et Cardiovasculaires, Université de Toulouse - UPS, Toulouse, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Abot
authors.affiliation: INSERM U1048, Institut des Maladies Métaboliques et Cardiovasculaires, Université de Toulouse - UPS, Toulouse, France.
authors.forename: Coralie
authors.initials: C
authors.lastname: Fontaine
authors.affiliation: INSERM U1048, Institut des Maladies Métaboliques et Cardiovasculaires, Université de Toulouse - UPS, Toulouse, France.
authors.forename: Mélissa
authors.initials: M
authors.lastname: Buscato
authors.affiliation: INSERM U1048, Institut des Maladies Métaboliques et Cardiovasculaires, Université de Toulouse - UPS, Toulouse, France.
authors.forename: Romain
authors.initials: R
authors.lastname: Solinhac
authors.affiliation: Institut de Recherche en Santé Environnement et Travail, IRSET, INSERM U1085, Team TREC, Biosit, Université de Rennes I, Rennes, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Flouriot
authors.affiliation: INSERM U1048, Institut des Maladies Métaboliques et Cardiovasculaires, Université de Toulouse - UPS, Toulouse, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Fabre
authors.affiliation: INSERM U1048, Institut des Maladies Métaboliques et Cardiovasculaires, Université de Toulouse - UPS, Toulouse, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Drougard
authors.affiliation: Department for Cancer Research, University of Chicago, Chicago, IL, USA.
authors.forename: Shyamala
authors.initials: S
authors.lastname: Rajan
authors.affiliation: Department for Cancer Research, University of Chicago, Chicago, IL, USA.
authors.forename: Muriel
authors.initials: M
authors.lastname: Laine
authors.affiliation: CNRS and Université de Toulouse, IPBS, Toulouse, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Milon
authors.affiliation: CNRS and Université de Toulouse, IPBS, Toulouse, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Muller
authors.affiliation: INSERM U1083, CNRS UMR 6214, Université d'Angers, Angers, France.
authors.forename: Daniel
authors.initials: D
authors.lastname: Henrion
authors.affiliation: INSERM U1048, Institut des Maladies Métaboliques et Cardiovasculaires, Université de Toulouse - UPS, Toulouse, France.
authors.forename: Marine
authors.initials: M
authors.lastname: Adlanmerini
authors.affiliation: INSERM U1048, Institut des Maladies Métaboliques et Cardiovasculaires, Université de Toulouse - UPS, Toulouse, France.
authors.forename: Marie-Cécile
authors.initials: MC
authors.lastname: Valéra
authors.affiliation: APHP, Unité de Gynécologie Endocrinienne, Université Paris Descartes, Paris, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Gompel
authors.affiliation: Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA-cancer), Université de Liège, Liège, Belgique.
authors.forename: Céline
authors.initials: C
authors.lastname: Gerard
authors.affiliation: Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA-cancer), Université de Liège, Liège, Belgique.
authors.forename: Christel
authors.initials: C
authors.lastname: Péqueux
authors.affiliation: Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA-cancer), Université de Liège, Liège, Belgique.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Mestdagt
authors.affiliation: INP, ENVT, Université de Toulouse, Toulouse, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Raymond-Letron
authors.affiliation: INSERM U1048, Institut des Maladies Métaboliques et Cardiovasculaires, Université de Toulouse - UPS, Toulouse, France.
authors.forename: Claude
authors.initials: C
authors.lastname: Knauf
authors.affiliation: Institut de Recherche en Santé Environnement et Travail, IRSET, INSERM U1085, Team TREC, Biosit, Université de Rennes I, Rennes, France.
authors.forename: François
authors.initials: F
authors.lastname: Ferriere
authors.affiliation: INSERM U1048, Institut des Maladies Métaboliques et Cardiovasculaires, Université de Toulouse - UPS, Toulouse, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Valet
authors.affiliation: INSERM U1048, Institut des Maladies Métaboliques et Cardiovasculaires, Université de Toulouse - UPS, Toulouse, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Gourdy
authors.affiliation: Departments of Molecular and Integrative Biology and Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
authors.forename: Benita S
authors.initials: BS
authors.lastname: Katzenellenbogen
authors.affiliation: Departments of Molecular and Integrative Biology and Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Katzenellenbogen
authors.affiliation: INSERM U1048, Institut des Maladies Métaboliques et Cardiovasculaires, Université de Toulouse - UPS, Toulouse, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Lenfant
authors.affiliation: Department for Cancer Research, University of Chicago, Chicago, IL, USA.
authors.forename: Geoffrey L
authors.initials: GL
authors.lastname: Greene
authors.affiliation: Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA-cancer), Université de Liège, Liège, Belgique.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Foidart
authors.affiliation: INSERM U1048, Institut des Maladies Métaboliques et Cardiovasculaires, Université de Toulouse - UPS, Toulouse, France Jean-Francois.Arnal@inserm.fr.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Arnal
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002462:Cell Membrane / Q000187:drug effects* / Q000378:metabolism; D002467:Cell Nucleus / Q000187:drug effects* / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D004953:Estetrol / Q000737:chemistry / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D007150:Immunohistochemistry; D061986:MCF-7 Cells; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008958:Models, Molecular; D015394:Molecular Structure; D010052:Ovariectomy; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014599:Uterus / Q000187:drug effects* / Q000378:metabolism
chemical_list: D047628:Estrogen Receptor alpha; D004953:Estetrol
keywords: endothelium; estetrol; estrogen receptor; uterus