Neijenhuis, S., Bajrami, I., Miller, R., Lord, C. J., Ashworth, A. (2013) Identification of miRNA modulators to PARP inhibitor response. DNA REPAIR, 12 (6). pp. 394-402. ISSN 1568-7864

Full text not available from this repository.

Abstract

Based on the principle of synthetic lethality, PARP inhibitors have been shown to be very effective in killing cells deficient in homologous recombination (HR), such as those bearing mutations in BRCA1/2. However, questions regarding their wider use persist and other determinants of responsiveness to PARP inhibitor remain to be fully explored. MicroRNAs (miRNAs) are small non-coding RNAs, which serve as post-transcriptional regulators of gene expression and are involved in a wide variety of cellular processes, including the DNA damage response (DDR). However, little is known about whether miRNAs might influence sensitivity to PARP inhibitors. To investigate this, we performed a high throughput miRNA mimetic screen, which identified several miRNAs whose over-expression results in sensitization to the clinical PARP inhibitor olaparib. In particular, our findings indicate that hsa-miR-107 and hsa-miR-222 regulate the DDR and sensitise tumour cells to olaparib by repressing expression of RAD51, thus impairing DSB repair by HR. Moreover, elevated expression of hsa-miR-107 has been observed in a subset of ovarian clear cell carcinomas, which correlates with PARP inhibitor sensitivity and reduced RAD51 expression. Taken together, these observations raise the possibility that these miRNAs could be used as biomarkers to identify patients that may benefit from treatment with PARP inhibitors. (c) 2013 Elsevier B.V. All rights reserved.

Item Type:	Article
Authors (ICR Faculty only):	Ashworth, Alan and Lord, Chris
All Authors:	Neijenhuis, S., Bajrami, I., Miller, R., Lord, C. J., Ashworth, A.
Additional Information:	ISI Document Delivery No.: 162TV Times Cited: 0 Cited Reference Count: 38 Neijenhuis, Sari Bajrami, Ilirjana Miller, Rowan Lord, Christopher J. Ashworth, Alan Breast Cancer Research Foundation; Breakthrough Breast Cancer; European Union as part of the FP7 programme "DDRESPONSE"; NHS We thank the Breast Cancer Research Foundation and Breakthrough Breast Cancer for funding this work as well as the European Union as part of the FP7 programme "DDRESPONSE". We also thank Thermo Fisher Scientific and Biomarin for the kind provision of reagents. We acknowledge NHS funding to the Royal Marsden/NIHR Biomedical Research Centre. Elsevier science bv Amsterdam
Uncontrolled Keywords:	PARP Olaparib miRNA RAD51 Radiation microrna targets poly(adp-ribose) polymerase rna interference cancer-therapy breast-cancer mutant-cells dna-damage repair sensitivity genes
Research teams:	ICR divisions > Breast Cancer Research > Gene Function ICR divisions > Molecular Pathology > Gene Function
Depositing User:	Alexander Smithson
Date Deposited:	15 Jul 2013 12:16
Last Modified:	15 Jul 2013 12:16
URI:	http://publications.icr.ac.uk/id/eprint/12573

Actions (login required)

View Item