PloS one, 2014-06, Vol.9 (6), p.e100041
2014
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- Autor(en) / Beteiligte
- Titel
- Effect of MRE11 loss on PARP-inhibitor sensitivity in endometrial cancer in vitro
- Ist Teil von
- PloS one, 2014-06, Vol.9 (6), p.e100041
- Ort / Verlag
- United States: Public Library of Science
- Erscheinungsjahr
- 2014
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- To evaluate the frequency of MRE11/RAD50/NBS1 (MRN)-complex loss of protein expression in endometrial cancers (EC) and to determine whether loss of MRE11 renders the cancer cells sensitive to Poly(ADP-ribose) polymerase (PARP)-inhibitory treatment. MRN expression was examined in 521 samples of endometrial carcinomas and in 10 cancer cell lines. A putative mutation hotspot in the form of an intronic poly(T) allele in MRE11 was sequenced in selected cases (n = 26). Sensitivity to the PARP-inhibitor, BMN673 was tested in colony formation assays before and after MRE11 silencing using siRNA. Homologous recombination (HR) DNA repair was evaluated by RAD51-foci formation assay upon irradiation and drug treatment. Loss of MRE11 protein was found in 30.7% of EC tumours and significantly associated with loss of RAD50, NBS1 and mismatch repair protein expression. One endometrial cell line showed a markedly reduced MRE11 expression due to a homozygous poly(T) mutation of MRE11, thereby exhibiting an increased sensitivity to BMN673. MRE11 depletion sensitizes MRE11 expressing EC cell lines to the treatment with BMN673. The increased sensitivity to PARP-inhibition correlates with reduced RAD51 foci formation upon ionizing radiation in MRE11-depleted cells. Loss of the MRE11 protein predicts sensitivity to PARP-inhibitor sensitivity in vitro, defining it as an additional synthetic lethal gene with PARP. The high incidence of MRE11 loss in ECs can be potentially exploited for PARP-inhibitor therapy. Furthermore, MRE11 protein expression using immunohistochemistry could be investigated as a predictive biomarker for PARP-inhibitor treatment.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1932-6203eISSN: 1932-6203DOI: 10.1371/journal.pone.0100041Titel-ID: cdi_plos_journals_1978560978
- Format
- –
- Schlagworte
- Adenosine diphosphate, Biology and life sciences, Biomarkers, Biomarkers, Pharmacological - metabolism, Biotechnology, Breast cancer, Cancer, Cancer therapies, Carcinoma, Carcinoma, Endometrioid - diagnosis, Carcinoma, Endometrioid - genetics, Carcinoma, Endometrioid - metabolism, Carcinoma, Endometrioid - pathology, Chemotherapy, Colorectal cancer, Deoxyribonucleic acid, DNA, DNA Mismatch Repair - drug effects, DNA Mismatch Repair - genetics, DNA repair, DNA-Binding Proteins - genetics, DNA-Binding Proteins - metabolism, Drug Resistance, Neoplasm - genetics, Endometrial cancer, Endometrial Neoplasms - diagnosis, Endometrial Neoplasms - genetics, Endometrial Neoplasms - metabolism, Endometrial Neoplasms - pathology, Endometrium, Female, Gene Knockdown Techniques, Genes, Gynecology, Homologous recombination, Homology, Humans, Immunohistochemistry, Inhibitors, Ionizing radiation, Irradiation, Medical prognosis, Medicine and Health Sciences, Mismatch repair, Monosaccharides, MRE11 Homologue Protein, MRE11 protein, Mutation, Mutation hot spots, Pathology, Poly(ADP-ribose), Poly(ADP-ribose) polymerase, Poly(ADP-ribose) Polymerase Inhibitors - pharmacology, Prognosis, Rad51 Recombinase - genetics, Rad51 Recombinase - metabolism, Radiation, Radiation therapy, Recombinational DNA Repair - drug effects, Recombinational DNA Repair - genetics, Repair, Research and Analysis Methods, Ribose, Sensitivity, Sensitivity analysis, siRNA, Tumor cell lines, Tumor Cells, Cultured, Tumors, Uterine cancer