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Published on: December 20, 2024
Anti-Tumoral Effects of Anti-Progestins in a Patient-Derived Breast Cancer Xenograft Model
Nathalie Esber1,2,3, Clément Cherbonnier4, Michèle Resche-Rigon3
1Inserm UMR-S 1185, Fac Med Paris Sud, Université Paris-Saclay, 63 rue Gabriel Péri, 94276, Le, Kremlin-Bicêtre, France.
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.
Insights
New progesterone receptor (PR) antagonists, ulipristal acetate (UPA) and APR19, show significant anti-tumor activity in preclinical breast cancer models. These drugs reduce tumor growth and proliferation, suggesting potential for hormone-dependent breast cancer therapy.
Area of Science:
- Oncology
- Endocrinology
- Pharmacology
Background:
- Breast cancer often depends on hormones like estrogen and progesterone.
- Resistance to estrogen-targeting drugs occurs in about 10% of cases.
- Progesterone receptor (PR) signaling plays a mitogenic role in breast cancer.
Purpose of the Study:
- To evaluate the anti-tumor activity of ulipristal acetate (UPA) and a novel PR antagonist (APR19).
- To investigate the efficacy of these PR modulators in a patient-derived breast tumor xenograft model.
Main Methods:
- Utilized a preclinical model with patient-derived breast tumor (HBCx-34) xenografted in nude mice.
- Administered UPA, APR19, or vehicle for 42 days, monitoring tumor weight, growth, and expression of key proteins.
- Assessed cell proliferation markers (Ki-67, Cyclin D1, PCNA) and apoptosis marker (PARP).
Main Results:
- UPA and APR19 significantly reduced tumor weight by 30% compared to vehicle.
- UPA treatment led to a 40% retardation in tumor growth and increased proliferation markers.
- APR19 increased tumor necrosis and reduced PR and estrogen receptor alpha expression, suggesting distinct mechanisms.
Conclusions:
- UPA and APR19 demonstrate significant in vivo anti-tumor activity against human breast cancer.
- These PR antagonists exhibit anti-proliferative and pro-apoptotic effects.
- Findings support the potential of anti-progestin therapies for breast cancer treatment.
