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 ß gene is localized to chromosome 8p12-p11 and encodes a key DNA base excision repair protein. Pol ß may be a tumour suppressor and involved in breast cancer pathogenesis. We conducted the first and the largest study to comprehensively evaluate pol ß in breast cancer. We investigated pol ß gene copy number changes in two cohorts (n = 128 &n = 1952), pol ß mRNA expression in two cohorts (n = 249 &n = 1952) and pol ß protein expression in two cohorts (n = 1406 &n = 252). Artificial neural network analysis for pol ß interacting genes was performed in 249 tumours. For mechanistic insights, pol ß gene copy number changes, mRNA and protein levels were investigated together in 128 tumours and validated in 1952 tumours. Low pol ß mRNA expression as well as low pol ß 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 ß protein remains associated with aggressive phenotype and poor survival (ps < 0.001). Artificial neural network analysis revealed ER as a top pol ß interacting gene. Mechanistically, there was strong positive correlation between pol ß gene copy number changes and pol ß mRNA expression (p < 0.0000001) and between pol ß mRNA and pol ß protein expression (p < 0.0000001). This is the first study to provide evidence that pol ß deficiency is linked to aggressive breast cancer and may have prognostic and predictive significance in patients.
