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miR-139-5p modulates radiotherapy resistance in breast cancer by repressing multiple gene networks of DNA repair and ROS defense


Radiotherapy is essential to the treatment of most solid tumors and acquired or innate resistance to this therapeutic modality is a major clinical problem. Here we show that miR-139-5p is a potent modulator of radiotherapy response in breast cancer via its regulation of genes involved in multiple DNA repair and reactive oxygen species defense pathways. Treatment of breast cancer cells with a miR-139-5p mimic strongly synergized with radiation both in vitro and in vivo, resulting in significantly increased oxidative stress, accumulation of unrepaired DNA damage, and induction of apoptosis. Several miR-139-5p target genes were also strongly predictive of outcome in radiotherapy-treated patients across multiple independent breast cancer cohorts. These prognostically relevant miR-139-5p target genes were used as companion biomarkers to identify radioresistant breast cancer xenografts highly amenable to sensitization by cotreatment with a miR-139-5p mimetic.Significance: The microRNA described in this study offers a potentially useful predictive biomarker of radiosensitivity in solid tumors and a generally applicable druggable target for tumor radiosensitization. Cancer Res; 78(2); 501-15. (c)2017 AACR.

Type Journal
ISBN 1538-7445 (Electronic) 0008-5472 (Linking)
Authors Pajic, M.; Froio, D.; Daly, S.; Doculara, L.; Millar, E.; Graham, P. H.; Drury, A.; Steinmann, A.; de Bock, C. E.; Boulghourjian, A.; Zaratzian, A.; Carroll, S.; Toohey, J.; O'Toole, S. A.; Harris, A. L.; Buffa, F. M.; Gee, H. E.; Hollway, G. E.; Molloy, T. J.
Responsible Garvan Author A/Prof Marina Pajic
Published Date 2018-01-15
Published Volume 78
Published Issue 2
Published Pages 501-515
Status Published in-print
DOI 10.1158/0008-5472.CAN-16-3105
URL link to publisher's version