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Mol Oncol. 2014 May;8(3):520-32. doi: 10.1016/j.molonc.2014.01.001. Epub 2014 Jan 10.

DNA polymerase β deficiency is linked to aggressive breast cancer: a comprehensive analysis of gene copy number, mRNA and protein expression in multiple cohorts.

Author information

1
Department of Oncology, Nottingham University Hospitals, Nottingham NG51PB, UK.
2
Department of Oncology, University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK; Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.
3
School of Science and Technology, Nottingham Trent University, Clifton Campus, Nottingham NG11 8NS, UK.
4
Division of Pathology, School of Molecular Medical Sciences, University of Nottingham, Nottingham University Hospitals, Nottingham NG51PB, UK.
5
Department of Oncology, Nottingham University Hospitals, Nottingham NG51PB, UK; Division of Oncology, School of Medicine, University of Nottingham, Nottingham NG51PB, UK. Electronic address: srinivasan.madhusudan@nottingham.ac.uk.

Abstract

Short arm of chromosome 8 is a hot spot for chromosomal breaks, losses and amplifications in breast cancer. Although such genetic changes may have phenotypic consequences, the identity of candidate gene(s) remains to be clearly defined. Pol β gene is localized to chromosome 8p12-p11 and encodes a key DNA base excision repair protein. Pol β may be a tumour suppressor and involved in breast cancer pathogenesis. We conducted the first and the largest study to comprehensively evaluate pol β in breast cancer. We investigated pol β gene copy number changes in two cohorts (n = 128 &n = 1952), pol β mRNA expression in two cohorts (n = 249 &n = 1952) and pol β protein expression in two cohorts (n = 1406 &n = 252). Artificial neural network analysis for pol β interacting genes was performed in 249 tumours. For mechanistic insights, pol β gene copy number changes, mRNA and protein levels were investigated together in 128 tumours and validated in 1952 tumours. Low pol β mRNA expression as well as low pol β protein expression was associated high grade, lymph node positivity, pleomorphism, triple negative, basal-like phenotypes and poor survival (ps < 0.001). In oestrogen receptor (ER) positive sub-group that received tamoxifen, low pol β protein remains associated with aggressive phenotype and poor survival (ps < 0.001). Artificial neural network analysis revealed ER as a top pol β interacting gene. Mechanistically, there was strong positive correlation between pol β gene copy number changes and pol β mRNA expression (p < 0.0000001) and between pol β mRNA and pol β protein expression (p < 0.0000001). This is the first study to provide evidence that pol β deficiency is linked to aggressive breast cancer and may have prognostic and predictive significance in patients.

KEYWORDS:

Breast cancer; Pol β; Predictive factor; Prognostic factor

PMID:
24462520
PMCID:
PMC5528629
DOI:
10.1016/j.molonc.2014.01.001
[Indexed for MEDLINE]
Free PMC Article
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