Titre
MAGI1 Prevents Senescence and Promotes the DNA Damage Response in ER+ Breast Cancer.
Type
article
Institution
UNIL/CHUV/Unisanté + institutions partenaires
Périodique
Auteur(s)
Wörthmüller, J.
Auteure/Auteur
Disler, S.
Auteure/Auteur
Pradervand, S.
Auteure/Auteur
Richard, F.
Auteure/Auteur
Haerri, L.
Auteure/Auteur
Ruiz Buendía, G.A.
Auteure/Auteur
Fournier, N.
Auteure/Auteur
Desmedt, C.
Auteure/Auteur
Rüegg, C.
Auteure/Auteur
Liens vers les personnes
Liens vers les unités
ISSN
2073-4409
Statut éditorial
Publié
Date de publication
2023-07-25
Volume
12
Numéro
15
Première page
1929
Peer-reviewed
Oui
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: epublish
Publication Status: epublish
Résumé
MAGI1 acts as a tumor suppressor in estrogen receptor-positive (ER <sup>+</sup> ) breast cancer (BC), and its loss correlates with a more aggressive phenotype. To identify the pathways and events affected by MAGI1 loss, we deleted the MAGI1 gene in the ER <sup>+</sup> MCF7 BC cell line and performed RNA sequencing and functional experiments in vitro. Transcriptome analyses revealed gene sets and biological processes related to estrogen signaling, the cell cycle, and DNA damage responses affected by MAGI1 loss. Upon exposure to TNF-α/IFN-γ, MCF7 MAGI1 KO cells entered a deeper level of quiescence/senescence compared with MCF7 control cells and activated the AKT and MAPK signaling pathways. MCF7 MAGI1 KO cells exposed to ionizing radiations or cisplatin had reduced expression of DNA repair proteins and showed increased sensitivity towards PARP1 inhibition using olaparib. Treatment with PI3K and AKT inhibitors (alpelisib and MK-2206) restored the expression of DNA repair proteins and sensitized cells to fulvestrant. An analysis of human BC patients' transcriptomic data revealed that patients with low MAGI1 levels had a higher tumor mutational burden and homologous recombination deficiency. Moreover, MAGI1 expression levels negatively correlated with PI3K/AKT and MAPK signaling, which confirmed our in vitro observations. Pharmacological and genomic evidence indicate HDACs as regulators of MAGI1 expression. Our findings provide a new view on MAGI1 function in cancer and identify potential treatment options to improve the management of ER <sup>+</sup> BC patients with low MAGI1 levels.
PID Serval
serval:BIB_6334A3F41720
PMID
Open Access
Oui
Date de création
2023-08-14T13:47:12.517Z
Date de création dans IRIS
2025-05-21T02:25:50Z
Fichier(s)![Vignette d'image]()
En cours de chargement...
Nom
37566008_BIB_6334A3F41720.pdf
Version du manuscrit
published
Licence
https://creativecommons.org/licenses/by/4.0
Taille
3.99 MB
Format
Adobe PDF
PID Serval
serval:BIB_6334A3F41720.P001
URN
urn:nbn:ch:serval-BIB_6334A3F417200
Somme de contrôle
(MD5):c70646726ac0ece382f0f9467d4e7528