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MAGI1 Prevents Senescence and Promotes the DNA Damage Response in ER(+) Breast Cancer
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 f...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10417439/ https://www.ncbi.nlm.nih.gov/pubmed/37566008 http://dx.doi.org/10.3390/cells12151929 |
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author | Wörthmüller, Janine Disler, Simona Pradervand, Sylvain Richard, François Haerri, Lisa Ruiz Buendía, Gustavo A. Fournier, Nadine Desmedt, Christine Rüegg, Curzio |
author_facet | Wörthmüller, Janine Disler, Simona Pradervand, Sylvain Richard, François Haerri, Lisa Ruiz Buendía, Gustavo A. Fournier, Nadine Desmedt, Christine Rüegg, Curzio |
author_sort | Wörthmüller, Janine |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-10417439 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-104174392023-08-12 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 Cells Article 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. MDPI 2023-07-25 /pmc/articles/PMC10417439/ /pubmed/37566008 http://dx.doi.org/10.3390/cells12151929 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Wörthmüller, Janine Disler, Simona Pradervand, Sylvain Richard, François Haerri, Lisa Ruiz Buendía, Gustavo A. Fournier, Nadine Desmedt, Christine Rüegg, Curzio MAGI1 Prevents Senescence and Promotes the DNA Damage Response in ER(+) Breast Cancer |
title | MAGI1 Prevents Senescence and Promotes the DNA Damage Response in ER(+) Breast Cancer |
title_full | MAGI1 Prevents Senescence and Promotes the DNA Damage Response in ER(+) Breast Cancer |
title_fullStr | MAGI1 Prevents Senescence and Promotes the DNA Damage Response in ER(+) Breast Cancer |
title_full_unstemmed | MAGI1 Prevents Senescence and Promotes the DNA Damage Response in ER(+) Breast Cancer |
title_short | MAGI1 Prevents Senescence and Promotes the DNA Damage Response in ER(+) Breast Cancer |
title_sort | magi1 prevents senescence and promotes the dna damage response in er(+) breast cancer |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10417439/ https://www.ncbi.nlm.nih.gov/pubmed/37566008 http://dx.doi.org/10.3390/cells12151929 |
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