Studies of apurinic/apyrimidinic endonuclease/ref-1 expression in epithelial ovarian cancer: correlations with tumor progression and platinum resistance.
OBJECTIVE
A crucial step in the DNA base excision repair pathway involves the cleavage of an apurinic/apyrimidinic site by an apurinic/apyrimidinic endonuclease (APE). The major APE in mammalian cells is APE/ref-1, a multifunctional enzyme that acts not only as a DNA repair enzyme but as a redox-modifying factor for a variety of transcription factors. The purpose of this study is to determine whether APE/ref-1 expression differs with ovarian cancer progression and metastasis and in platinum-resistant disease.


METHODS
Ovarian tissue sections were obtained from the Cooperative Human Tissue Network for studies of APE/ref-1 expression and the metastatic process and from our institutional Department of Pathology for studies of APE/ref-1 expression and platinum resistance. Tissue microsections from formalin-fixed, paraffin-embedded specimens of epithelial ovarian cancers were stained using a monoclonal antibody to APE/ref-1 followed by standard immunohistochemical techniques. Slides were then analyzed for the percentage of positively staining nuclei as well as staining intensity using a blinded coding system.


RESULTS
All epithelial ovarian cancers expressed APE/ref-1. There were no significant differences in the percentage or intensity of nuclear staining in primary tumors from patients with early- versus advanced-stage disease or in primary tumors versus metastasis from patients with advanced disease. Both platinum-sensitive and platinum-refractory tumors demonstrated a range from minimal to high intensity staining nuclei with a median value of 2+ staining on a scale of 0-3+. The median value for the percentage of nuclei involved was 70% in the platinum-sensitive group and 90% in the platinum-refractory group (P = 0.118).


CONCLUSIONS
APE/ref-1 expression is ubiquitous among epithelial ovarian cancers and is unaltered with the metastatic process. APE/ref-1 expression does not appear to differ between platinum-sensitive and platinum-refractory ovarian cancers and thus is not a useful biomarker for platinum resistance. Combined with evidence that APE/ref-1 expression and function may not be equivalent in all cell types and tissues, future work will investigate APE/ref-1 as a potential therapeutic target.
Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
Sarah
S
Freitas
David H
DH
Moore
Helen
H
Michael
Mark R
MR
Kelley
D000911:Antibodies, Monoclonal / Q000737:chemistry; D014408:Biomarkers, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D004260:DNA Repair; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000096:biosynthesis*; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D009362:Neoplasm Metastasis; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy* / Q000201:enzymology*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000201:enzymology*; D017671:Platinum Compounds / Q000627:therapeutic use*
D000911:Antibodies, Monoclonal; D014408:Biomarkers, Tumor; D017671:Platinum Compounds; C085108:APEX1 protein, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase