biostudies-literatureGupta MBreast Cancer Research FoundationHHS | NIH | National Institute of General Medical SciencesHHS | NIH | National Cancer InstituteHHS | NIH | National Center for Advancing Translational Sciences (NCATS)HHS | NIH | National Cancer Institute (NCI)HHS | NIH | National Center for Advancing Translational SciencesHHS | NIH | National Institute of General Medical Sciences (NIGMS)e2207898120https://www.ebi.ac.uk/biostudies/studies/S-EPMC10104532biostudies-literatureUnknown120(15)Breast cancer (BC) metastasis involves cancer stem cells (CSCs) and their regulation by micro-RNAs (miRs), but miR targeting of the translation machinery in CSCs is poorly explored. We therefore screened miR expression levels in a range of BC cell lines, comparing non-CSCs to CSCs, and focused on miRs that target translation and protein synthesis factors. We describe a unique translation regulatory axis enacted by reduced expression of miR-183 in breast CSCs, which we show targets the eIF2Bδ subunit of guanine nucleotide exchange factor eIF2B, a regulator of protein synthesis and the integrated stress response (ISR) pathway. We report that reduced expression of miR-183 greatly increases eIF2Bδ protein levels, preventing strong induction of the ISR and eIF2α phosphorylation, by preferential interaction with P-eIF2α. eIF2Bδ overexpression is essential for BC cell invasion, metastasis, maintenance of metastases, and breast CSC expansion in animal models. Increased expression of eIF2Bδ, a site of action of the drug ISRIB that also prevents ISR signaling, is essential for breast CSC maintenance and metastatic capacity.Proceedings of the National Academy of Sciences of the United States of AmericaeIF2Bδ blocks the integrated stress response and maintains eIF2B activity and cancer metastasis by overexpression in breast cancer stem cells.PMC10104532R01CA248397P30CA016087BCRF-21-146T32 CA9161-41UL1TR00038R01CA178509GM066704Katsara OGeter PAWalters BASchneider RJGupta MGranados Blanco KfalseeIF2Bδ blocks the integrated stress response and maintains eIF2B activity and cancer metastasis by overexpression in breast cancer stem cells.Breast cancer (BC) metastasis involves cancer stem cells (CSCs) and their regulation by micro-RNAs (miRs), but miR targeting of the translation machinery in CSCs is poorly explored. We therefore screened miR expression levels in a range of BC cell lines, comparing non-CSCs to CSCs, and focused on miRs that target translation and protein synthesis factors. We describe a unique translation regulatory axis enacted by reduced expression of miR-183 in breast CSCs, which we show targets the eIF2Bδ subunit of guanine nucleotide exchange factor eIF2B, a regulator of protein synthesis and the integrated stress response (ISR) pathway. We report that reduced expression of miR-183 greatly increases eIF2Bδ protein levels, preventing strong induction of the ISR and eIF2α phosphorylation, by preferential interaction with P-eIF2α. eIF2Bδ overexpression is essential for BC cell invasion, metastasis, maintenance of metastases, and breast CSC expansion in animal models. Increased expression of eIF2Bδ, a site of action of the drug ISRIB that also prevents ISR signaling, is essential for breast CSC maintenance and metastatic capacity.2023-01-01T00:00:00Z2023 Apr2024-11-15T21:58:39.701Z2024-11-15T21:58:39.701ZS-EPMC101045323701485010.1073/pnas.2207898120