Anti-Tumoral Effects of Anti-Progestins in a Patient-Derived Breast Cancer Xenograft Model
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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.
KeywordsProgesterone Receptor Proliferate Cell Nuclear Antigen Progesterone Receptor Expression Proliferate Cell Nuclear Antigen Expression Ulipristal Acetate
- PR antagonists
This study was supported by fundings from Institut National de la Santé et de la Recherche Médicale (Inserm), Université Paris Sud, and a grant from La Ligue Nationale Contre le Cancer (to FJ and ML). The authors would like to thank Pr Jean-Daniel Brion, Dr Marie-Edith Rafestin-Oblin, and Dr Junaid Ali Khan for their help and comments during the initial phase of this work.
The funder HRA Pharma provided grant together with the national agency for Research (ANRT/HRA pharma CIFRE, i.e., Conventions Industrielles de Formation par la Recherche, in English Research Training Industrial Grant Contract) for [NE], support in the form of salary for one author [MRR], but did not have any additional role in the study design, data collection and analysis, or preparation of the manuscript.
Compliance with Ethical Standards
Conflict of Interest
MRR is an employee of HRA Pharma.
NE is a recipient of a joint ANRT/HRA Pharma grant.
NCB is a member of the European board of Gedeon Richter, without personal income.
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