Lack of MRE11-RAD50-NBS1 (MRN) complex detection occurs frequently in low-grade epithelial ovarian cancer

BMC Cancer. 2017 Jan 10;17(1):44. doi: 10.1186/s12885-016-3026-2.

Abstract

Background: BRCA1/2-deficient ovarian carcinomas are recognized as target for Poly (ADP-ribose) polymerase (PARP) inhibitors. BRCA1 and BRCA2 proteins are involved in homologous recombination repair of double-strand DNA breaks. The relevance of other homologous recombination repair proteins, e.g. MRE11, RAD50, NBS1 (MRN complex) in ovarian carcinomas is unclear. The objective of this study was to investigate the prevalence of lack of MRE11, RAD50, NBS1 protein detection in epithelial ovarian cancer (EOC).

Methods: A tissue microarray (TMA) with 134 EOC was immunohistochemically evaluated for MRE11, RAD50 and NBS1. Data was analysed for associations with clinicopathological parameters, histological subtype, patient overall survival and mismatch repair (MMR) protein status. Sensitivity towards the PARP inhibitor BMN673 was tested in two ovarian cancer cell lines (TOV-21 and OVTOKO) using colony formation assays.

Results: Lack of MRN complex protein detection was seen in 41% (55/134) of EOC and was more frequent in low-grade (57.6%; 19/33) than in high-grade EOC (18.8%; 36/101; n = 134; p = 0.04). There was an association with the ovarian carcinoma subtype (60.3%; 35/58 lack of detection in type I versus 26.3%; 20/76 in type II; n = 134; p < 0.001) as well as undetectable DNA mismatch repair proteins MLH1 and MSH2 (89.3%; 25/28; n = 131; p < 0.001). MRE11 knockdown led to moderately increased sensitivity towards the PARP inhibitor BMN673 in one ovarian carcinoma cell line in vitro.

Conclusions: Frequent lack of MRE11, RAD50, NBS1 protein detection in type I human ovarian carcinomas is observed in EOC and our data suggests further investigation regarding sensitivity to PARP-inhibition in tumours lacking MRE11 expression.

Keywords: MRN complex; Ovarian cancer; PARP inhibitor.

MeSH terms

  • Acid Anhydride Hydrolases
  • Adenocarcinoma, Clear Cell / drug therapy
  • Adenocarcinoma, Clear Cell / metabolism
  • Adenocarcinoma, Clear Cell / pathology
  • Adenocarcinoma, Mucinous / drug therapy
  • Adenocarcinoma, Mucinous / metabolism
  • Adenocarcinoma, Mucinous / pathology
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Biomarkers, Tumor / metabolism*
  • Cell Cycle Proteins / metabolism*
  • Cystadenocarcinoma, Serous / drug therapy
  • Cystadenocarcinoma, Serous / metabolism
  • Cystadenocarcinoma, Serous / pathology
  • DNA Repair Enzymes / metabolism*
  • DNA-Binding Proteins / metabolism*
  • Endometrial Neoplasms / drug therapy
  • Endometrial Neoplasms / metabolism
  • Endometrial Neoplasms / pathology
  • Female
  • Follow-Up Studies
  • Humans
  • MRE11 Homologue Protein
  • Middle Aged
  • Neoplasm Grading
  • Neoplasm Recurrence, Local / drug therapy
  • Neoplasm Recurrence, Local / metabolism
  • Neoplasm Recurrence, Local / pathology*
  • Nuclear Proteins / metabolism*
  • Ovarian Neoplasms / drug therapy
  • Ovarian Neoplasms / metabolism
  • Ovarian Neoplasms / pathology*
  • Prognosis
  • Survival Rate

Substances

  • Biomarkers, Tumor
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • MRE11 protein, human
  • NBN protein, human
  • Nuclear Proteins
  • MRE11 Homologue Protein
  • Acid Anhydride Hydrolases
  • Rad50 protein, human
  • DNA Repair Enzymes