Skip to Main content Skip to Navigation
Theses

PRMT1, un nouveau corégulateur de la signalisation de la progestérone dans le cancer du sein

Abstract : Breast cancer progression is mainly driven by estrogen and progesterone signalling and therapies modulating oestrogen‘s action have improved the survival of ER+ cancer patients. As progesterone receptor (PR) is an ER target gene, its expression in breast cancer was considered as a predictive marker of ER functionality. However, recent studies are converging on the concept that PR can directly affect ER functions in breast cancer cells1. Activated PR can redirect ER to novel chromatin binding sites associated with cell differentiation and apoptosis, leading to a potential improvement of the tumour response to anti-oestrogen therapies. In considering the differential effects of progesterone in breast cancer, it is important to define the variable might influence progesterone pathway and the downstream mediators involved in this signalling. Recently, Beato and al reported that, in breast cancer cells, the unliganded form of PR (non-activated with progesterone) bind to genomic sites and target a repressive complex containing enzyme modifying chromatin as the demethylase LSD1 or the Heterochromatin Protein 1 (HP1γ)2. Under hormonal treatment, this complex is displaced, which makes it possible to recruit coactivators and associated cofactors, which modify the structure of the local chromatin and cause the activation or repression of the target genes of PR. In addition, cellular response to progesterone is also regulated by receptor post-translational modifications that may affect its stability, its subcellular localization and its interactions with regulators. In our study, we demonstrated for the first time that PR is methylated on arginine residues, by the arginine methyltransferase PRMT1. We identified as target the arginine 637 (R637), a conserved arginine among nuclear receptor superfamily, located in the DNA-binding domain of the receptor. By in vitro and in vivo approaches, we are studying the impact of PRMT1 on PR signalling pathways. In T47D breast cancer cells, we demonstrated that PR interacts with PRMT1, mainly in the nucleus. Of interest, PRMT1 interacts with PR in the nucleus in absence of hormone stimulation and it appears as a new member of the repressive complex on a subset of progesterone inducible genes. Our results also indicate that PRMT1 expression affects PR transcriptional activity and PRMT1 knockdown disrupts the rapid activation of protein kinase pathway after progestin stimulation. The production of an antibody directed against the methylated form of PR allowed us to specify that methylated-PR is localized in the nucleus of cells and was found only after progesterone treatment. Furthermore, PRMT1 depletion and mutation of R637 resulted in an inhibition of a subset of PR-regulated genes which led to retarded cell growth.Our data reveal the impact of PRMT1 expression on PR pathways and provide evidence for the asymmetric arginine dimethylation of PR. We therefore demonstrate that methylation on arginine residues could be a novel control mechanism in the response to progesterone in mammary tumor cells
Document type :
Theses
Complete list of metadatas

Cited literature [54 references]  Display  Hide  Download

https://tel.archives-ouvertes.fr/tel-02407422
Contributor : Abes Star :  Contact
Submitted on : Thursday, December 12, 2019 - 3:05:09 PM
Last modification on : Wednesday, June 10, 2020 - 6:42:06 PM
Long-term archiving on: : Friday, March 13, 2020 - 8:51:06 PM

File

TH2019MALBETEAULUCIE.pdf
Version validated by the jury (STAR)

Identifiers

  • HAL Id : tel-02407422, version 1

Collections

Citation

Lucie Malbéteau. PRMT1, un nouveau corégulateur de la signalisation de la progestérone dans le cancer du sein. Cancer. Université de Lyon, 2019. Français. ⟨NNT : 2019LYSE1178⟩. ⟨tel-02407422⟩

Share

Metrics

Record views

190

Files downloads

278