Open AccessThe uterine and vascular actions of estetrol delineate a distinctive profile of estrogen receptor α modulation, uncoupling nuclear and membrane activation
Author(s) -
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 MarieCécile,
Gompel Anne,
Gerard Céline,
Péqueux Christel,
Mestdagt Mélanie,
RaymondLetron Isabelle,
Knauf Claude,
Ferriere François,
Valet Philippe,
Gourdy Pierre,
Katzenellenbogen Benita S,
Katzenellenbogen John A,
Lenfant Françoise,
Greene Geoffrey L,
Foidart JeanMichel,
Arnal JeanFrançois
Publication year - 2014
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201404112
Subject(s) - endocrinology , medicine , nuclear receptor , estrogen , nuclear receptor coactivator 1 , microbiology and biotechnology , estrogen receptor , receptor , coactivator , biology , chemistry , biochemistry , cancer , breast cancer , transcription factor , gene
Estetrol (E 4 ) 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 ( ER α) ligand‐binding domain bound to 17β‐estradiol (E 2 ) and E 4 are very similar, as well as their capacity to activate the two activation functions AF ‐1 and AF ‐2 and to recruit the coactivator SRC 3. In vivo administration of high doses of E 4 stimulated uterine gene expression, epithelial proliferation, and prevented atheroma, three recognized nuclear ER α actions. However, E 4 failed to promote endothelial NO synthase activation and acceleration of endothelial healing, two processes clearly dependent on membrane‐initiated steroid signaling ( MISS ). Furthermore, E 4 antagonized E 2 MISS ‐dependent effects in endothelium but also in MCF ‐7 breast cancer cell line. This profile of ER α activation by E 4 , uncoupling nuclear and membrane activation, characterizes E 4 as a selective ER modulator which could have medical applications that should now be considered further.