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Studies of Apurinic/Apyrimidinic Endonuclease/ref-1 Expression in Epithelial Ovarian Cancer

Correlations with Tumor Progression and Platinum Resistance

Departments of Obstetrics and Gynecology [S. F., D. H. M.], Pathology [H. M.], and Pediatrics [M. R. K.], Indiana University School of Medicine, Indianapolis, Indiana 46202

ABSTRACT

Purpose: 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.

Experimental Design: 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.

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