title: Ulipristal Acetate Inhibits Progesterone Receptor Isoform A-Mediated Human Breast Cancer Proliferation and BCl2-L1 Expression.
abstract: The progesterone receptor (PR) with its isoforms and ligands are involved in breast tumorigenesis and prognosis. We aimed at analyzing the respective contribution of PR isoforms, PRA and PRB, in breast cancer cell proliferation in a new estrogen-independent cell based-model, allowing independent PR isoforms analysis. We used the bi-inducible human breast cancer cell system MDA-iPRAB. We studied the effects and molecular mechanisms of action of progesterone (P4) and ulipristal acetate (UPA), a new selective progesterone receptor modulator, alone or in combination. P4 significantly stimulated MDA-iPRA expressing cells proliferation. This was associated with P4-stimulated expression of the anti-apoptotic factor BCL2-L1 and enhanced recruitment of PRA, SRC-1 and RNA Pol II onto the +58 kb PR binding motif of the BCL2-L1 gene. UPA decreased cell proliferation and repressed BCL2-L1 expression in the presence of PRA, correlating with PRA and SRC1 but not RNA Pol II recruitment. These results bring new information on the mechanism of action of PR ligands in controlling breast cancer cell proliferation through PRA in an estrogen independent model. Evaluation of PR isoforms ratio, as well as molecular signature studies based on PRA target genes could be proposed to facilitate personalized breast cancer therapy. In this context, UPA could be of interest in endocrine therapy. Further confirmation in the clinical setting is required.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche-Scientifique 1185, Faculté de Médecine Paris Sud, Le Kremlin-Bicêtre, France; Université Paris-Sud, Faculté de Médecine Paris Sud, Unité Mixte de Recherche-Scientifique 1185, Le Kremlin-Bicêtre, France; HRA-Pharma, Paris, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Esber
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche-Scientifique 1185, Faculté de Médecine Paris Sud, Le Kremlin-Bicêtre, France; Université Paris-Sud, Faculté de Médecine Paris Sud, Unité Mixte de Recherche-Scientifique 1185, Le Kremlin-Bicêtre, France.
authors.forename: Florian
authors.initials: F
authors.lastname: Le Billan
authors.affiliation: HRA-Pharma, Paris, France.
authors.forename: Michèle
authors.initials: M
authors.lastname: Resche-Rigon
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche-Scientifique 1185, Faculté de Médecine Paris Sud, Le Kremlin-Bicêtre, France; Université Paris-Sud, Faculté de Médecine Paris Sud, Unité Mixte de Recherche-Scientifique 1185, Le Kremlin-Bicêtre, France.
authors.forename: Hugues
authors.initials: H
authors.lastname: Loosfelt
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche-Scientifique 1185, Faculté de Médecine Paris Sud, Le Kremlin-Bicêtre, France; Université Paris-Sud, Faculté de Médecine Paris Sud, Unité Mixte de Recherche-Scientifique 1185, Le Kremlin-Bicêtre, France; Service d'Endocrinologie et des Maladies de la Reproduction, assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Le Kremlin Bicêtre, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Lombès
authors.affiliation: Service de Gynécologie Obstétrique Médecine de la Reproduction, Hôpitaux Universitaires Est Parisien site Tenon, AP-HP, Paris, France; Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche-Scientifique 938, Centre de Recherche Saint Antoine, Université Pierre et Marie Curie, Paris, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Chabbert-Buffet
mesh_terms: D001943:Breast Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D009649:Norpregnadienes / Q000494:pharmacology*; D011374:Progesterone / Q000494:pharmacology; D011980:Receptors, Progesterone / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D051020:bcl-X Protein / Q000235:genetics*
chemical_list: D009649:Norpregnadienes; D011980:Receptors, Progesterone; D051020:bcl-X Protein; C101118:progesterone receptor A; D011374:Progesterone; C555622:ulipristal acetate