Single-strand selective monofunctional uracil-DNA glycosylase (SMUG1) deficiency is linked to aggressive breast cancer and predicts response to adjuvant therapy

Uracil in DNA is an important cause of mutagenesis. SMUG1 is a uracil-DNA glycosylase that removes uracil through base excision repair. SMUG1 also processes radiation-induced oxidative base damage as well as 5-fluorouracil incorporated into DNA during chemotherapy. We investigated SMUG1 mRNA expression in 249 primary breast cancers. SMUG1 protein expression was investigated in 1,165 breast tumours randomised into two cohorts [training set ( n = 583) and test set ( n = 582)]. SMUG1 and chemotherapy response was also investigated in a series of 315 ER-negative tumours ( n = 315). For mechanistic insights, SMUG1 was correlated to biomarkers of aggressive phenotype, DNA repair, cell cycle and apoptosis. Low SMUG1 mRNA expression was associated with adverse disease specific survival ( p = 0.008) and disease-free survival ( p = 0.008). Low SMUG1 protein expression (25 %) was associated with high histological grade ( p < 0.0001), high mitotic index ( p < 0.0001), pleomorphism ( p < 0.0001), glandular de-differentiation ( p = 0.0001), absence of hormonal receptors (ER−/PgR−/AR) ( p < 0.0001), presence of basal-like ( p < 0.0001) and triple-negative phenotypes ( p < 0.0001). Low SMUG1 protein expression was associated with loss of BRCA1 ( p < 0.0001), ATM ( p < 0.0001) and XRCC1 ( p < 0.0001). Low p27 ( p < 0.0001), low p21 ( p = 0.023), mutant p53 ( p = 0.037), low MDM2 ( p < 0.0001), low MDM4 ( p = 0.004), low Bcl-2 ( p = 0.001), low Bax ( p = 0.003) and high MIB1 ( p < 0.0001) were likely in low SMUG1 tumours. Low SMUG1 protein expression was associated with poor prognosis in univariate ( p < 0.001) and multivariate analysis ( p < 0.01). In ER+ cohort that received adjuvant endocrine therapy, low SMUG1 protein expression remains associated with poor survival ( p < 0.01). In ER− cohort that received adjuvant chemotherapy, low SMUG1 protein expression is associated with improved survival ( p = 0.043). Our study suggests that low SMUG1 expression may correlate to adverse clinicopathological features and predict response to adjuvant therapy in breast cancer.