title: Single-strand selective monofunctional uracil-DNA glycosylase (SMUG1) deficiency is linked to aggressive breast cancer and predicts response to adjuvant therapy.
abstract: 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.
authors.affiliation: Department of Oncology, Nottingham University Hospitals, Nottingham, NG51PB, UK.
authors.forename: Tarek M A
authors.initials: TM
authors.lastname: Abdel-Fatah
authors.forename: Nada
authors.initials: N
authors.lastname: Albarakati
authors.forename: Lara
authors.initials: L
authors.lastname: Bowell
authors.forename: Devika
authors.initials: D
authors.lastname: Agarwal
authors.forename: Paul
authors.initials: P
authors.lastname: Moseley
authors.forename: Claire
authors.initials: C
authors.lastname: Hawkes
authors.forename: Graham
authors.initials: G
authors.lastname: Ball
authors.forename: Stephen
authors.initials: S
authors.lastname: Chan
authors.forename: Ian O
authors.initials: IO
authors.lastname: Ellis
authors.forename: Srinivasan
authors.initials: S
authors.lastname: Madhusudan
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D017024:Chemotherapy, Adjuvant; D015331:Cohort Studies; D005260:Female; D006801:Humans; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D010641:Phenotype; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D016896:Treatment Outcome; D047368:Tumor Burden; D051981:Uracil-DNA Glycosidase / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D012333:RNA, Messenger; D011960:Receptors, Estrogen; C498095:SMUG1 protein, human; D051981:Uracil-DNA Glycosidase