Single-strand selective monofunctional uracil-DNA glycosylase (SMUG1) deficiency is linked to aggressive breast cancer and predicts response to adjuvant therapy.
Abdel-Fatah TMA., Albarakati N., Bowell L., Agarwal D., Moseley P., Hawkes C., Ball G., Chan S., Ellis IO., Madhusudan S.
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.