title: Effect of MRE11 loss on PARP-inhibitor sensitivity in endometrial cancer in vitro.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Gynaecology, University Hospital of Zurich, Zurich, Switzerland.
authors.forename: Romana
authors.initials: R
authors.lastname: Koppensteiner
authors.affiliation: Division of Gynaecology, University Hospital of Zurich, Zurich, Switzerland.
authors.forename: Eleftherios P
authors.initials: EP
authors.lastname: Samartzis
authors.affiliation: Institute of Surgical Pathology, University Hospital of Zurich, Zurich, Switzerland.
authors.forename: Aurelia
authors.initials: A
authors.lastname: Noske
authors.affiliation: Institute of Surgical Pathology, University Hospital of Zurich, Zurich, Switzerland.
authors.forename: Adriana
authors.initials: A
authors.lastname: von Teichman
authors.affiliation: Division of Gynaecology, University Hospital of Zurich, Zurich, Switzerland.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Dedes
authors.affiliation: Division of Gynaecology, University Hospital of Zurich, Zurich, Switzerland.
authors.forename: Myriam
authors.initials: M
authors.lastname: Gwerder
authors.affiliation: Division of Gynaecology, University Hospital of Zurich, Zurich, Switzerland.
authors.forename: Patrick
authors.initials: P
authors.lastname: Imesch
authors.affiliation: Institute of Surgical Pathology, University Hospital of Zurich, Zurich, Switzerland.
authors.forename: Kristian
authors.initials: K
authors.lastname: Ikenberg
authors.affiliation: Institute of Surgical Pathology, University Hospital of Zurich, Zurich, Switzerland.
authors.forename: Holger
authors.initials: H
authors.lastname: Moch
authors.affiliation: Division of Gynaecology, University Hospital of Zurich, Zurich, Switzerland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Fink
authors.affiliation: Division of Gynaecology, University Hospital of Zurich, Zurich, Switzerland.
authors.forename: Manuel
authors.initials: M
authors.lastname: Stucki
authors.affiliation: Division of Gynaecology, University Hospital of Zurich, Zurich, Switzerland.
authors.forename: Konstantin J
authors.initials: KJ
authors.lastname: Dedes
mesh_terms: D054316:Biomarkers, Pharmacological / Q000378:metabolism; D018269:Carcinoma, Endometrioid / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D053843:DNA Mismatch Repair / Q000187:drug effects / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D016889:Endometrial Neoplasms / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D000076228:MRE11 Homologue Protein; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000494:pharmacology*; D011379:Prognosis; D051135:Rad51 Recombinase / Q000235:genetics / Q000378:metabolism; D059767:Recombinational DNA Repair / Q000187:drug effects / Q000235:genetics; D014407:Tumor Cells, Cultured
chemical_list: D054316:Biomarkers, Pharmacological; D004268:DNA-Binding Proteins; C121766:MRE11 protein, human; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D051135:Rad51 Recombinase; D000076228:MRE11 Homologue Protein