title: Anti-Tumoral Effects of Anti-Progestins in a Patient-Derived Breast Cancer Xenograft Model.
abstract: Breast cancer is a hormone-dependent disease in which estrogen signaling targeting drugs fail in about 10 % due to resistance. Strong evidences highlighted the mitogen role of progesterone, its ligands, and the corresponding progesterone receptor (PR) isoforms in mammary carcinoma. Several PR antagonists have been synthesized; however, some of them are non-selective and led to side or toxic effects. Herein, we evaluated the anti-tumor activity of a commercially available PR modulator, ulipristal acetate (UPA), and a new selective and passive PR antagonist "APR19" in a novel preclinical approach based on patient-derived breast tumor (HBCx-34) xenografted in nude mice. As opposed to P4 that slightly reduces tumor volume, UPA and APR19 treatment for 42 days led to a significant 30 % reduction in tumor weight, accompanied by a significant 40 % retardation in tumor growth upon UPA exposure while a 1.5-fold increase in necrotic areas was observed in APR19-treated tumors. Interestingly, PR expression was upregulated by a 2.5-fold factor in UPA-treated tumors while APR19 significantly reduced expression of both PR and estrogen receptor α, indicating a potential distinct molecular mechanism among PR antagonists. Cell proliferation was clearly reduced in UPA group compared to vehicle conditions, as revealed by the significant reduction in Ki-67, Cyclin D1, and proliferating cell nuclear antigen (PCNA) expression. Likewise, an increase in activated, cleaved poly(ADP-ribose) polymerase (PARP) expression was also demonstrated upon UPA exposure. Collectively, our findings provide direct in vivo evidence for anti-progestin-mediated control of human breast cancer growth, given their anti-proliferative and pro-apoptotic activities, supporting a potential role in breast cancer therapy.
authors.affiliation: Inserm UMR-S 1185, Fac Med Paris Sud, Université Paris-Saclay, 63 rue Gabriel Péri, 94276, Le, Kremlin-Bicêtre, France.|University Paris-Sud, Université Paris-Saclay, UMR-S1185, 94276, Le, Kremlin-Bicêtre, France.|HRA-Pharma, 15 rue Béranger, 75003, Paris, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Esber
authors.affiliation: Service d'Anatomie et Cytologie Pathologiques, Hôpitaux Universitaires Est Parisien site Tenon, Assistance Publique-Hôpitaux de Paris, 4 Rue de la Chine, 75020, Paris, France.
authors.forename: Clément
authors.initials: C
authors.lastname: Cherbonnier
authors.affiliation: HRA-Pharma, 15 rue Béranger, 75003, Paris, France.
authors.forename: Michèle
authors.initials: M
authors.lastname: Resche-Rigon
authors.affiliation: Centre National de la Recherche Scientifique, BioCIS, Faculté de Pharmacie, 92296, Châtenay-Malabry, France.
authors.forename: Abdallah
authors.initials: A
authors.lastname: Hamze
authors.affiliation: Centre National de la Recherche Scientifique, BioCIS, Faculté de Pharmacie, 92296, Châtenay-Malabry, France.
authors.forename: Mouad
authors.initials: M
authors.lastname: Alami
authors.affiliation: Inserm UMR-S 1185, Fac Med Paris Sud, Université Paris-Saclay, 63 rue Gabriel Péri, 94276, Le, Kremlin-Bicêtre, France.|University Paris-Sud, Université Paris-Saclay, UMR-S1185, 94276, Le, Kremlin-Bicêtre, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Fagart
authors.affiliation: Inserm UMR-S 1185, Fac Med Paris Sud, Université Paris-Saclay, 63 rue Gabriel Péri, 94276, Le, Kremlin-Bicêtre, France.|University Paris-Sud, Université Paris-Saclay, UMR-S1185, 94276, Le, Kremlin-Bicêtre, France.
authors.forename: Hugues
authors.initials: H
authors.lastname: Loosfelt
authors.affiliation: Inserm UMR-S 1185, Fac Med Paris Sud, Université Paris-Saclay, 63 rue Gabriel Péri, 94276, Le, Kremlin-Bicêtre, France.|University Paris-Sud, Université Paris-Saclay, UMR-S1185, 94276, Le, Kremlin-Bicêtre, France.|Service d'Endocrinologie et des Maladies de la Reproduction, Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, 94275, 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, Assistance Publique-Hôpitaux de Paris, 4 Rue de la Chine, 75020, Paris, France. nathalie.chabbert-buffet@aphp.fr.|Inserm UMR-S 938, Centre de Recherche Saint Antoine, Université Pierre et Marie Curie, 75012, Paris, France. nathalie.chabbert-buffet@aphp.fr.|Réseau CALG (Cancer Associé a la Grossesse), 75 012, Paris, France. nathalie.chabbert-buffet@aphp.fr.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Chabbert-Buffet
mesh_terms: D000736:Androstenes / Q000008:administration & dosage* / Q000494:pharmacology; D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006718:Homosteroids / Q000008:administration & dosage* / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009649:Norpregnadienes / Q000008:administration & dosage* / Q000494:pharmacology; D011980:Receptors, Progesterone / Q000235:genetics / Q000378:metabolism*; D016896:Treatment Outcome; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C585339:APR19 compound; D000736:Androstenes; D006718:Homosteroids; D009649:Norpregnadienes; D011980:Receptors, Progesterone; C555622:ulipristal acetate