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Ulipristal Acetate Inhibits Progesterone Receptor Isoform A-Mediated Human Breast Cancer Proliferation and BCl2-L1 Expression.

Esber N, Le Billan F, Resche-Rigon M, Loosfelt H, Lombès M, Chabbert-Buffet N - PLoS ONE (2015)

Bottom Line: P4 significantly stimulated MDA-iPRA expressing cells proliferation.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.Further confirmation in the clinical setting is required.

View Article: PubMed Central - PubMed

Affiliation: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche-Scientifique 1185, Faculté de Médecine Paris Sud, Le Kremlin-Bicêtre, France; Université Paris-Sud, Faculté de Médecine Paris Sud, Unité Mixte de Recherche-Scientifique 1185, Le Kremlin-Bicêtre, France; HRA-Pharma, Paris, France.

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 BCL2-L1 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.

No MeSH data available.


Related in: MedlinePlus

Ulipristal acetate (UPA) inhibits P4-dependent MDA-iPRA cell proliferation.MDA-iPRA cultured on 96-well plates, were treated with vehicle or P4 (1 nM) and/or UPA (1 μM) in fresh steroid-free medium containing DMSO or RSL1 (0.5 μM) on day 0, 2 and 4. Cell proliferation assays were performed using CellTiter96H AqueousOne Solution as described in Materials and Methods. The 490 nm absorbance was determined on day 1, 3 and 5. Data are expressed as fold induction compared to vehicle condition arbitrarily set at 1, and are means ± SEM from five independent cell cultures (n = 6 for each experiment). ** indicates p<0.01 compared to the vehicle-treated cells for each MDA-iPRA cell line while xx indicates p<0.01 compared to the P4-treated cells (non-parametric Mann Whitney t-tests).
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pone.0140795.g002: Ulipristal acetate (UPA) inhibits P4-dependent MDA-iPRA cell proliferation.MDA-iPRA cultured on 96-well plates, were treated with vehicle or P4 (1 nM) and/or UPA (1 μM) in fresh steroid-free medium containing DMSO or RSL1 (0.5 μM) on day 0, 2 and 4. Cell proliferation assays were performed using CellTiter96H AqueousOne Solution as described in Materials and Methods. The 490 nm absorbance was determined on day 1, 3 and 5. Data are expressed as fold induction compared to vehicle condition arbitrarily set at 1, and are means ± SEM from five independent cell cultures (n = 6 for each experiment). ** indicates p<0.01 compared to the vehicle-treated cells for each MDA-iPRA cell line while xx indicates p<0.01 compared to the P4-treated cells (non-parametric Mann Whitney t-tests).

Mentions: We next examined the effect of the SPRM, UPA, on MDA-iPRA cell proliferation (Fig 2) and found that UPA at 1 μM alone or in association with P4 significantly inhibited cell proliferation as early as Day 3 (see also S2A Fig). This was consistent with our previous report showing that RU486 (Mifepristone) inhibits MDA-iPRA cell proliferation [6]. Of note, in the absence of PR, UPA has no effect, while UPA inhibited PRB-expressing cells and PRAB-expressing cells proliferation (S2B and S2C Fig). UPA has synergistic effects with P4 in MDA-iPRB cells.


Ulipristal Acetate Inhibits Progesterone Receptor Isoform A-Mediated Human Breast Cancer Proliferation and BCl2-L1 Expression.

Esber N, Le Billan F, Resche-Rigon M, Loosfelt H, Lombès M, Chabbert-Buffet N - PLoS ONE (2015)

Ulipristal acetate (UPA) inhibits P4-dependent MDA-iPRA cell proliferation.MDA-iPRA cultured on 96-well plates, were treated with vehicle or P4 (1 nM) and/or UPA (1 μM) in fresh steroid-free medium containing DMSO or RSL1 (0.5 μM) on day 0, 2 and 4. Cell proliferation assays were performed using CellTiter96H AqueousOne Solution as described in Materials and Methods. The 490 nm absorbance was determined on day 1, 3 and 5. Data are expressed as fold induction compared to vehicle condition arbitrarily set at 1, and are means ± SEM from five independent cell cultures (n = 6 for each experiment). ** indicates p<0.01 compared to the vehicle-treated cells for each MDA-iPRA cell line while xx indicates p<0.01 compared to the P4-treated cells (non-parametric Mann Whitney t-tests).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4608808&req=5

pone.0140795.g002: Ulipristal acetate (UPA) inhibits P4-dependent MDA-iPRA cell proliferation.MDA-iPRA cultured on 96-well plates, were treated with vehicle or P4 (1 nM) and/or UPA (1 μM) in fresh steroid-free medium containing DMSO or RSL1 (0.5 μM) on day 0, 2 and 4. Cell proliferation assays were performed using CellTiter96H AqueousOne Solution as described in Materials and Methods. The 490 nm absorbance was determined on day 1, 3 and 5. Data are expressed as fold induction compared to vehicle condition arbitrarily set at 1, and are means ± SEM from five independent cell cultures (n = 6 for each experiment). ** indicates p<0.01 compared to the vehicle-treated cells for each MDA-iPRA cell line while xx indicates p<0.01 compared to the P4-treated cells (non-parametric Mann Whitney t-tests).
Mentions: We next examined the effect of the SPRM, UPA, on MDA-iPRA cell proliferation (Fig 2) and found that UPA at 1 μM alone or in association with P4 significantly inhibited cell proliferation as early as Day 3 (see also S2A Fig). This was consistent with our previous report showing that RU486 (Mifepristone) inhibits MDA-iPRA cell proliferation [6]. Of note, in the absence of PR, UPA has no effect, while UPA inhibited PRB-expressing cells and PRAB-expressing cells proliferation (S2B and S2C Fig). UPA has synergistic effects with P4 in MDA-iPRB cells.

Bottom Line: P4 significantly stimulated MDA-iPRA expressing cells proliferation.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.Further confirmation in the clinical setting is required.

View Article: PubMed Central - PubMed

Affiliation: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche-Scientifique 1185, Faculté de Médecine Paris Sud, Le Kremlin-Bicêtre, France; Université Paris-Sud, Faculté de Médecine Paris Sud, Unité Mixte de Recherche-Scientifique 1185, Le Kremlin-Bicêtre, France; HRA-Pharma, Paris, France.

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 BCL2-L1 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.

No MeSH data available.


Related in: MedlinePlus