MAGI1 prevents senescence and promotes the DNA damage response in ER+ breast cancer
MAGI1 acts as tumor suppressor in estrogen receptor positive (ER+) breast cancer (BC) and its loss correlates with a more aggressive phenotype. To identify 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, cell cycle and DNA damage response affected by MAGI1 loss. Upon exposure to TNF-alpha/IFN-gamma, MCF7 MAGI1 KO cells entered a deeper level of quiescence/senescence than 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 with olaparib. Treatment with PI3K and AKT inhibitors (alpelisib and MK-2206) restored expression of DNA repair proteins and sensitized cells to fulvestrant. Analysis of human BC patients' transcriptomic data revealed that patients with low MAGI1 levels have a higher tumor mutational burden and homologous recombination deficiency. Also, MAGI1 expression levels correlate negatively with PI3K/AKT and MAPK signaling, confirming 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. Overall design: To identify pathways and events affected by MAGI1 loss, we deleted the MAGI1 gene by CRISPR/Cas9 technology in the ER+ MCF7 BC cell line and performed RNA-sequencing and functional experiments in vitro.