title: Adverse prognostic and predictive significance of low DNA-dependent protein kinase catalytic subunit (DNA-PKcs) expression in early-stage breast cancers.
abstract: DNA-dependent protein kinase catalytic subunit (DNA-PKcs), a serine threonine kinase belonging to the PIKK family (phosphoinositide 3-kinase-like-family of protein kinase), is a critical component of the non-homologous end-joining pathway required for the repair of DNA double-strand breaks. DNA-PKcs may be involved in breast cancer pathogenesis. We evaluated clinicopathological significance of DNA-PKcs protein expression in 1,161 tumours and DNA-PKcs mRNA expression in 1,950 tumours. We correlated DNA-PKcs to markers of aggressive phenotypes, DNA repair, apoptosis, cell cycle regulation and survival. Low DNA-PKcs protein expression was associated with higher tumour grade, higher mitotic index, tumour de-differentiation and tumour type (ps < 0.05). The absence of BRCA1, low XRCC1, low SMUG1, low APE1 and low Polβ was also more likely in low DNA-PKcs expressing tumours (ps < 0.05). Low DNA-PKcs protein expression was significantly associated with worse breast cancer-specific survival (BCSS) in univariate and multivariate analysis (ps < 0.01). At the mRNA level, similarly, low DNA-PKcs was associated with poor BCSS. In patients with ER-positive tumours who received endocrine therapy, low DNA-PKcs (protein and mRNA) was associated with poor survival. In ER-negative patients, low DNA-PKcs mRNA remains significantly associated with adverse outcome. Our study suggests that low DNA-PKcs expression may have prognostic and predictive significance in breast cancers.
authors: Department of Oncology, Nottingham University Hospitals, Nottingham, NG5 1PB, UK.
authors: Tarek
authors: T
authors: Abdel-Fatah
authors: Arvind
authors: A
authors: Arora
authors: Devika
authors: D
authors: Agarwal
authors: Paul
authors: P
authors: Moseley
authors: Christina
authors: C
authors: Perry
authors: Nicola
authors: N
authors: Thompson
authors: Andrew R
authors: AR
authors: Green
authors: Emad
authors: E
authors: Rakha
authors: Stephen
authors: S
authors: Chan
authors: Graham
authors: G
authors: Ball
authors: Ian O
authors: IO
authors: Ellis
authors: Srinivasan
authors: S
authors: Madhusudan
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality*; D020134:Catalytic Domain / Q000235:genetics*; D045744:Cell Line, Tumor; D051747:DNA-Activated Protein Kinase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D006801:Humans; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D011379:Prognosis; D054730:Protein Interaction Domains and Motifs / Q000235:genetics*; D047368:Tumor Burden
chemical_list: D014408:Biomarkers, Tumor; D051747:DNA-Activated Protein Kinase