Abstract
Aim of the studyTo 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.MethodsMRN 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.ResultsLoss 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.ConclusionLoss 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.
Highlights
Endometrial cancer (EC) is the fourth most common malignancy among women
The goal of this study is to show the frequency of loss of MRE11 and MRN-complex in EC and whether this leads to increased sensitivity to Poly(ADP-ribose) polymerase (PARP)-inhibitors exploiting MRE11 as a potential synthetic lethal gene
Expression loss of MRE11 significantly correlated with protein loss of the other MRN-complex members RAD50 and NBS1
Summary
Endometrial cancer (EC) is the fourth most common malignancy among women. The majority of ECs are diagnosed in early stage and are associated with very favourable overall prognosis [1]. EC is a heterogeneous disease with distinct histological and molecular characteristics [2]. EC have been classified into types I and II. This is based on the different histological properties (endometrioid vs non-endometrioid) and on the clinical prognosis (favourable vs poor) [2,3]. Novel molecular subgroups have been described in a way akin to breast cancer [5]. Based on their mutation profile and copy-number changes ECs are categorized into: the ultramutated, the hypermuted, the copy number low and the copy number high subgroup [5]
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