The uterine and vascular actions of estetrol delineate a distinctive profile of estrogen receptor alpha modulation, uncoupling nuclear and membrane activation.
[en] 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 alpha (ERalpha) ligand-binding domain bound to 17beta-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 ERalpha 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 ERalpha 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.
Disciplines :
Endocrinology, metabolism & nutrition
Author, co-author :
Abot, Anne
Fontaine, Coralie
Buscato, Melissa
Solinhac, Romain
Flouriot, Gilles
Fabre, Aurelie
Drougard, Anne
Rajan, Shyamala
Laine, Muriel
Milon, Alain
Muller, Isabelle
Henrion, Daniel
Adlanmerini, Marine
Valera, Marie-Cecile
Gompel, Anne
Gérard, Céline ; Université de Liège - ULiège > Département des sciences cliniques > Labo de biologie des tumeurs et du développement
Pequeux, Christel ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Département des sciences biomédicales et précliniques
Mestdagt, Melanie
Raymond-Letron, Isabelle
Knauf, Claude
Ferriere, Francois
Valet, Philippe
Gourdy, Pierre
Katzenellenbogen, Benita S.
Katzenellenbogen, John A.
Lenfant, Francoise
Greene, Geoffrey L.
Foidart, Jean-Michel ; Université de Liège - ULiège > Département des sciences cliniques > Gynécologie - Obstétrique
The uterine and vascular actions of estetrol delineate a distinctive profile of estrogen receptor alpha modulation, uncoupling nuclear and membrane activation.
Publication date :
2014
Journal title :
EMBO Molecular Medicine
ISSN :
1757-4676
eISSN :
1757-4684
Publisher :
Wiley-Blackwell, United Kingdom
Volume :
6
Issue :
10
Pages :
1328-46
Peer reviewed :
Peer Reviewed verified by ORBi
Commentary :
(c) 2014 The Authors. Published under the terms of the CC BY 4.0 license.
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