The uterine and vascular actions of estetrol delineate a distinctive profile of estrogen receptor α modulation, uncoupling nuclear and membrane activation. Issue 10 (11th September 2014)

• Record Type: Journal Article
• Authors: Abot, Anne; Fontaine, Coralie; Buscato, Mélissa; Solinhac, Romain; Flouriot, Gilles; Fabre, Aurélie; Drougard, Anne; Rajan, Shyamala; Laine, Muriel; Milon, Alain; Muller, Isabelle; Henrion, Daniel; Adlanmerini, Marine; Valéra, Marie‐Cécile; Gompel, Anne; Gerard, Céline; Péqueux, Christel; Mestdagt, Mélanie; Raymond‐Letron, Isabelle; Knauf, Claude; Ferriere, François; Valet, Philippe; Gourdy, Pierre; Katzenellenbogen, Benita S; Katzenellenbogen, John A; Lenfant, Françoise; Greene, Geoffrey L; Foidart, Jean‐Michel; Arnal, Jean‐François
• Is Part Of: EMBO molecular medicine. Volume 6:Issue 10(2014:Oct.)
• Page Start: 1328
• Page End: 1346
• Publication Date: 2014-09-11
• Subjects: Molecular biology -- Periodicals; Medical genetics -- Periodicals; Pathology, Molecular -- Periodicals; 616.04205
• DOI: 10.15252/emmm.201404112
• Languages: English
• ISSNs: 1757-4676

Abstract

<abstract abstract-type="main" id="emmm201404112-abs-0001"> <title>Abstract</title> <p>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. <italic>In vivo</italic> 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.</p> </abstract>