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

Anne Abot (1) , Coralie Fontaine , Mélissa Buscato (1) , Romain Solinhac (1) , Gilles Flouriot (2) , Aurelie J Fabre , Anne Drougard (1) , Shyamala Rajan , Muriel Laine , Alain Milon , Isabelle Muller , Daniel Henrion , Marine Adlanmerini (1) , Marie-Cécile Valéra (1) , Anne Gompel (3) , Céline Gerard , Christel Péqueux (1) , Mélanie Mestdagt (4) , Isabelle Raymond-Letron , Claude Knauf (1) , François Ferriere (2) , Philippe Valet , Pierre Gourdy (1) , Benita S Katzenellenbogen (5) , John A Katzenellenbogen , Françoise Lenfant (6) , Geoffrey L Greene , Jean-Michel Foidart (7) , Jean-François Arnal

1 I2MC - Institut des Maladies Métaboliques et Cardiovasculaires
2 Irset - Institut de recherche en santé, environnement et travail
3 Centre national de référence des angioedemes
4 Laboratory of Tumor and Developmental Biology
5 Department of Molecular and Integrative Physiology
6 I2MR - Institut de médecine moléculaire de Rangueil
7 Laboratoire de Biologie des Tumeurs et du Développement)

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.

Domains: Life Sciences [q-bio]

Anne Abot, Coralie Fontaine, Mélissa Buscato, Romain Solinhac, Gilles Flouriot, et al.. The uterine and vascular actions of estetrol delineate a distinctive profile of estrogen receptor α modulation, uncoupling nuclear and membrane activation.. EMBO Molecular Medicine, 2014, 6 (10), pp.1328-46. ⟨10.15252/emmm.201404112⟩. ⟨hal-01118028⟩