miR-139-5p Modulates Radiotherapy Resistance in Breast Cancer by Repressing Multiple Gene Networks of DNA Repair and ROS Defense.

Abstract

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. ©2017 AACR.

• Authors: Marina Pajic, Danielle Froio, Sheridan Daly, Louise Doculara, Ewan Millar, Peter H Graham, Alison Drury, Angela Steinmann, Charles E de Bock, Alice Boulghourjian, Anaiis Zaratzian, Susan Carroll, Joanne Toohey, Sandra A O'Toole, Adrian L Harris, Francesca M Buffa, Harriet E Gee, Georgina E Hollway, Timothy J Molloy
• Journal: Cancer research (Cancer Res) Vol. 78 Issue 2 Pg. 501-515 (01 15 2018) ISSN: 1538-7445 [Electronic] United States
• PMID: 29180477 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2017 American Association for Cancer Research.

Chemical References

• Biomarkers, Tumor
• MIRN139 microRNA, human
• MicroRNAs
• Reactive Oxygen Species

Topics

• Animals
• Apoptosis
• Biomarkers, Tumor (genetics)
• Breast Neoplasms (genetics, pathology, radiotherapy)
• Case-Control Studies
• Cell Proliferation
• DNA Damage (radiation effects)
• DNA Repair (radiation effects)
• Female
• Follow-Up Studies
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic (radiation effects)
• Gene Regulatory Networks (radiation effects)
• Humans
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• MicroRNAs (genetics)
• Neoplasm Recurrence, Local (genetics, pathology, radiotherapy)
• Prognosis
• Radiation Tolerance (genetics)
• Reactive Oxygen Species (metabolism)
• Survival Rate
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays