Journal
CELL REPORTS
Volume 21, Issue 12, Pages 3498-3513Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2017.11.096
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Funding
- University of Birmingham
- Breast Cancer Now [2014NovPR352]
- Medical Research Council (MRC) [MR/M009912/1]
- Circles of Influence scheme (University of Birmingham)
- Cancer Research UK [15938] Funding Source: researchfish
- Medical Research Council [MR/M009912/1] Funding Source: researchfish
- MRC [MR/M009912/1] Funding Source: UKRI
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Breast cancer progression, treatment resistance, and relapse are thought to originate from a small population of tumor cells, breast cancer stem cells (BCSCs). Identification of factors critical for BCSC function is therefore vital for the development of therapies. Here, we identify the argininemethyltransferase PRMT5 as a key in vitro and in vivo regulator of BCSC proliferation and self-renewal and establish FOXP1, a winged helix/forkhead transcription factor, as a critical effector of PRMT5-induced BCSC function. Mechanistically, PRMT5 recruitment to the FOXP1 promoter facilitates H3R2me2s, SET1 recruitment, H3K4me3, and gene expression. Our findings are clinically significant, as PRMT5 depletion within established tumor xenografts or treatment of patient-derived BCSCs with a pre-clinical PRMT5 inhibitor substantially reduces BCSC numbers. Together, our findings highlight the importance of PRMT5 in BCSC maintenance and suggest that small-molecule inhibitors of PRMT5 or downstream targets could be an effective strategy eliminating this cancer-causing population.
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