Journal
NATURE COMMUNICATIONS
Volume 5, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms6671
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Funding
- NIH [P30CA016672, R00CA138572, R01CA166051, R01CA181029, R44GM086937, R43GM100777, R01CA164346, U54CA151668]
- CPRIT Scholar Award [R1004]
- Developmental Research Award in Leukemia SPORE [CA100632]
- Center for Inflammation and Cancer
- Center for Genetics and Genomics
- Institutional Research Grant
- Sister Institution Network fund of MD Anderson Cancer Center
- Cancer Center Support Grant [P30CA016672]
- Gilbert H. Fletcher Chair
- Komen Foundation [KG101478]
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Tumour cells associated with therapy resistance (radioresistance and drug resistance) are likely to give rise to local recurrence and distant metastatic relapse. Recent studies revealed microRNA (miRNA)-mediated regulation of metastasis and epithelial-mesenchymal transition; however, whether specific miRNAs regulate tumour radioresistance and can be exploited as radiosensitizing agents remains unclear. Here we find that miR-205 promotes radiosensitivity and is downregulated in radioresistant subpopulations of breast cancer cells, and that loss of miR-205 is highly associated with poor distant relapse-free survival in breast cancer patients. Notably, therapeutic delivery of miR-205 mimics via nanoliposomes can sensitize the tumour to radiation in a xenograft model. Mechanistically, radiation suppresses miR-205 expression through ataxia telangiectasia mutated (ATM) and zinc finger E-box binding homeobox 1 (ZEB1). Moreover, miR-205 inhibits DNA damage repair by targeting ZEB1 and the ubiquitin-conjugating enzyme Ubc13. These findings identify miR-205 as a radiosensitizing miRNA and reveal a new therapeutic strategy for radioresistant tumours.
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