Physiologie et physiopathologie des effets membranaires du récepteur des œstrogènes alpha (ERα) dans la glande mammaire

Physiology et physiopathology of membrane estrogen receptor alpha (ERα) in mammary gland

• Auteur / Autrice : Laurine Gagniac
• Direction : Françoise Lenfant
• Type : Thèse de doctorat
• Discipline(s) : Physiopathologie
• Date : Soutenance le 05/03/2018
• Etablissement(s) : Toulouse 3
• Ecole(s) doctorale(s) : École doctorale Biologie Santé Biotechnologies (Toulouse)
• Partenaire(s) de recherche : Laboratoire : Institut des Maladies Métaboliques et Cardiovasculaires (Toulouse ; 2011-....)

Mots clés

Mots clés contrôlés

Homéostasie

Glande mammaire

Estrogènes

Mots clés libres

Glande mammaire

Œstrogènes

Récepteur des œstrogènes alpha

Cellules souches

Cancer du sein

Mammary gland

Estrogens

Estrogen receptor alpha

Estrogen receptor alpha

Résumé

It is well established that the 17-estradiol is involved in the development and homeostasis of reproductive and extra-reproductive tissues, particularly the mammary gland. Estradiol classically binds to Estrogen Receptor (ERα), which is a member of the nuclear receptor superfamily. ER mediates nuclear (transcription) and plasma membrane (signaling) ERα function. Interestingly, the membrane initiated steroid signaling (MISS) required a post translational modification of the receptor: palmitoylation of the human Cys-447 or the murine Cys-451 counterpart. The main objectives of my PhD thesis were to decipher the physiological role of membrane ERα in mammary gland development and to understand how the membrane ER signaling impact breast cancer. To do so, we used the transgenic mouse model C451A-ER in which the single point mutation (C451A) was introduced to abolish palmitoylation of ER (membrane addressing signal). We demonstrate that the point mutation of the palmitoylation site of ER alters the paracrine signaling of luminal epithelial cells and by consequence the repopulation properties of the mammary stem cells. We also studied the involvement of the membrane effects of the Estrogen Receptor ERα in the 17β-estradiol response dose of the mammary gland. Finally, by breeding the C451A-ER mice with the widely used transgenic mice model of tumorigenesis (PyMT), we provide the first evidence that the membrane ERα influences tumorigenesis. These findings pave the way on an unexpected role of non-genomic function of ERα in the mammary gland physiology and physiopathology.