Abstract
Human apurinic/apyrimidinic endonuclease 1 (APE1) is an essential protein for DNA base excision repair (BER) and redox regulation. The ability of cancer cells to recognize DNA damage and initiate DNA repair is an important mechanism for therapeutic resistance. Several recent studies have suggested that APE1 expression levels and/or subcellular dysregulation may be used to indicate the sensitivity of tumors to radiotherapy or chemotherapy. In this study, we assessed the prognostic significance of APE1 and differences in APE1 expression levels according to breast cancer molecular subtypes. We analyzed formalin-fixed, paraffin-embedded tumor tissue sections from 243 cases diagnosed as invasive breast cancer at Ewha Womans University Medical Center between January 2003 and December 2008. Immunohistochemistry was performed and the nuclear level of APE1 was scored by taking into account the percentage of positive cells. Medical records were reviewed to investigate clinicopathologic characteristics. We found that nuclear APE1 high-level expression (proportion ≥50%) in breast cancer showed a tendency towards unfavorable prognosis regarding disease-free survival (p = 0.093). However, there was no significant difference in overall survival between low and high-level expression groups (p = 0.294). Interestingly, within the Ki-67 low-level expression group, APE1 low-level expression was significantly associated with poor overall survival (p = 0.007). A significant positive correlation was observed between APE1 nuclear expression and estrogen receptor status (75.7% vs. 59.7%, p = 0.022). Also, the luminal A subtype was the most commonly observed breast cancer subtype in the APE1 high-level expression group (61.6% vs. 45.2%, p = 0.000). This study suggests that APE1 expression may be associated with breast cancer prognosis. In particular, its role as a prognostic factor would be significant for breast cancers with a low Ki-67 proliferation index. It is proposed that nuclear APE1 may be a novel target in breast cancer with a low proliferation rate to obtain better outcome.
Highlights
Human apurinic/apyrimidinic endonuclease 1 (APE1, called HAP1) is a multi-functional protein involved in DNA repair and redox regulation
APE1 is a class II apurinic apyrimidinic endonuclease that incises DNA to cause a nick in the backbone creating an AP-site, which acts as a recognition site for enzymes subsequently involved in the base excision repair (BER) pathway [1]
IHC, used to evaluate APE1 expression, revealed that staining intensity of the APE1 protein was strong in all 30 normal breast tissues
Summary
Human apurinic/apyrimidinic endonuclease 1 (APE1, called HAP1) is a multi-functional protein involved in DNA repair and redox regulation. An alternative name for APE1 is redox effector factor-1 (Ref1), because this protein was identified as a redox modulator of transcription factors (TFs) including Fos, Jun, nuclear factor-kB (NFkB), HIF-1a and p53 [2]. In addition to these activities, APE1 has specific roles in regulating cell fate and is involved in the control of different cellular process such as apoptosis, proliferation and differentiation [3]. The N-terminal domain is essential for the redox activity of APE1 while the Cterminus is essential for DNA repair activity [6]
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