| Autor: |
Esber N; 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., Cherbonnier C; 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., Resche-Rigon M; HRA-Pharma, 15 rue Béranger, 75003, Paris, France., Hamze A; Centre National de la Recherche Scientifique, BioCIS, Faculté de Pharmacie, 92296, Châtenay-Malabry, France., Alami M; Centre National de la Recherche Scientifique, BioCIS, Faculté de Pharmacie, 92296, Châtenay-Malabry, France., Fagart J; 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., Loosfelt H; 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., Lombès M; 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., Chabbert-Buffet N; 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. |
| Abstrakt: |
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. |
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