title: Clinicopathological significance of human apurinic/apyrimidinic endonuclease 1 (APE1) expression in oestrogen-receptor-positive breast cancer.
abstract: Oestrogen metabolites can induce oxidative DNA base damage and generate potentially mutagenic apurinic sites (AP sites) in the genomic DNA. If unrepaired, mutagenic AP sites could drive breast cancer pathogenesis and aggressive phenotypes. Human apurinic/apyrimidinic endonuclease 1 (APE1) is a key DNA base excision repair (BER) protein and essential for processing AP sites generated either directly by oestrogen metabolites or during BER of oxidative base damage. Our hypothesis is that altered APE1 expression may be associated with aggressive tumour biology and impact upon clinical outcomes in breast cancer. In the current study, we have investigated APE1 protein expression in a large cohort of breast cancers (n = 1285) and correlated to clinicopathological features and survival outcomes. Low APE1 protein expression was associated with high histological grade (p < 0.000001), high mitotic index (p < 0.000001), glandular de-differentiation (p < 0.000001), pleomorphism (p = 0.003), absence of hormonal receptors (ER-/PgR-/AR-) (p < 0.0001) and presence of triple negative phenotype (p = 0.001). Low APE1 protein expression was associated with loss of BRCA1, low XRCC1, low FEN1, low SMUG1 and low pol β (ps < 0.0001). High MIB1 (p = 0.048), bcl-2 negativity (p < 0.0001) and low TOP2A (p < 0.0001) were likely in low APE1 tumours. In the ER-positive sub-group, specifically, low APE1 remains significantly associated with high histological grade, high mitotic index, glandular de-differentiation (ps < 0.00001) and poor breast cancer specific survival (p = 0.007). In the ER-positive cohort that received adjuvant endocrine therapy, low APE1 protein expression is associated with poor survival (p = 0.006). In multivariate analysis, low APE1 remains independently associated with poor survival in ER-positive tumours (p = 0.048). We conclude that low APE1 expression may have prognostic and predictive significance in ER-positive breast cancers.
authors.affiliation: Department of Oncology, Nottingham University Hospitals, Nottingham, NG51PB, UK.
authors.forename: Tarek M A
authors.initials: TM
authors.lastname: Abdel-Fatah
authors.forename: Christina
authors.initials: C
authors.lastname: Perry
authors.forename: Paul
authors.initials: P
authors.lastname: Moseley
authors.forename: Kerstie
authors.initials: K
authors.lastname: Johnson
authors.forename: Arvind
authors.initials: A
authors.lastname: Arora
authors.forename: Stephen
authors.initials: S
authors.lastname: Chan
authors.forename: Ian O
authors.initials: IO
authors.lastname: Ellis
authors.forename: Srinivasan
authors.initials: S
authors.lastname: Madhusudan
mesh_terms: D014408:Biomarkers, Tumor / Q000096:biosynthesis; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D004249:DNA Damage / Q000235:genetics; D004260:DNA Repair / Q000235:genetics*; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000096:biosynthesis*; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D061986:MCF-7 Cells; D060787:Neoplasm Grading; D011379:Prognosis; D011960:Receptors, Estrogen / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; D011960:Receptors, Estrogen; C085108:APEX1 protein, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase