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 BCL 2 -L 1 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.

MicroRNA and Transcription Factor Gene Regulatory Network Analysis Reveals Key Regulatory Elements Associated with Prostate Cancer Progression

“…However, the role of PGR in the prostate cancer has not been fully understood yet. Regulation of BCL2 by PGR through direct binding to its promoter has been reported before [40,41]. BCL2 is an anti-apoptotic onco-protein.…”

Ulipristal Acetate Interferes With Actin Remodeling Induced by 17β-Estradiol and Progesterone in Human Endometrial Stromal Cells

“…Studies suggest that UPA is a promising endocrine therapy for hormone-sensitive tumors like breast or endometrial cancer. Particularly, Esber et al, found anti-proliferative and pro-apoptotic effects in patient-derived breast cancer xenografts in nude mice exposed to UPA ( 44 , 45 ). Other groups observed that UPA is able to reverse E2 and P4 actions by decreasing breast cell proliferation and hormone receptor expression on BRCA1-mutated breast tissue xenografted in mice; suggesting that a subset of women with BRCA1 mutations could be candidates for UPA treatment as a preventive breast cancer strategy ( 46 ).…”

Progesterone Receptor Isoforms, Nuclear Corepressor-1 and Steroid Receptor Coactivator-1 and B-Cell Lymphoma 2 and Akt and Akt Phosphorylation Status in Uterine Myomas after Ulipristal Acetate Treatment: A Systematic Immunohistochemical Evaluation

“…Interestingly, UPA displays different activity in vitro, depending on PR isoforms, with PR-A playing a preponderant role [48]. In 2D cultures, UPA also specifically controls PR expression, repressing PR-B but elevating PR-A protein levels in myoma cells [49], while it increases levels of both PR-A and PR-B in breast cancer cells [50]. We found no difference in either PR-A or PR-B expression in UPA-treated tissue compared to the control group, however, contrasting with these in vitro studies.…”