Your browser doesn't support javascript.
loading
MAGI1 Prevents Senescence and Promotes the DNA Damage Response in ER+ Breast Cancer.
Wörthmüller, Janine; Disler, Simona; Pradervand, Sylvain; Richard, François; Haerri, Lisa; Ruiz Buendía, Gustavo A; Fournier, Nadine; Desmedt, Christine; Rüegg, Curzio.
Afiliación
  • Wörthmüller J; Laboratory of Experimental and Translational Oncology, Department of Oncology, Microbiology and Immunology (OMI), Faculty of Science and Medicine, University of Fribourg, 1700 Fribourg, Switzerland.
  • Disler S; Laboratory of Experimental and Translational Oncology, Department of Oncology, Microbiology and Immunology (OMI), Faculty of Science and Medicine, University of Fribourg, 1700 Fribourg, Switzerland.
  • Pradervand S; Lausanne Genomic Technologies Facility (LGTF), University of Lausanne, 1015 Lausanne, Switzerland.
  • Richard F; Laboratory for Translational Breast Cancer Research, KU Leuven, 3000 Leuven, Belgium.
  • Haerri L; Laboratory of Experimental and Translational Oncology, Department of Oncology, Microbiology and Immunology (OMI), Faculty of Science and Medicine, University of Fribourg, 1700 Fribourg, Switzerland.
  • Ruiz Buendía GA; Translational Data Science-Facility, AGORA Cancer Research Center, Swiss Institute of Bioinformatics (SIB), Bugnon 25A, 1005 Lausanne, Switzerland.
  • Fournier N; Translational Data Science-Facility, AGORA Cancer Research Center, Swiss Institute of Bioinformatics (SIB), Bugnon 25A, 1005 Lausanne, Switzerland.
  • Desmedt C; Laboratory for Translational Breast Cancer Research, KU Leuven, 3000 Leuven, Belgium.
  • Rüegg C; Laboratory of Experimental and Translational Oncology, Department of Oncology, Microbiology and Immunology (OMI), Faculty of Science and Medicine, University of Fribourg, 1700 Fribourg, Switzerland.
Cells ; 12(15)2023 07 25.
Article en En | MEDLINE | ID: mdl-37566008
MAGI1 acts as a tumor suppressor in estrogen receptor-positive (ER+) 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+ 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+ BC patients with low MAGI1 levels.
Asunto(s)
Palabras clave
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias de la Mama / Guanilato-Quinasas Tipo de estudio: Prognostic_studies Límite: Female / Humans Idioma: En Revista: Cells Año: 2023 Tipo del documento: Article País de afiliación: Suiza Pais de publicación: Suiza
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias de la Mama / Guanilato-Quinasas Tipo de estudio: Prognostic_studies Límite: Female / Humans Idioma: En Revista: Cells Año: 2023 Tipo del documento: Article País de afiliación: Suiza Pais de publicación: Suiza