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

ABDEL-FATAH, T.M.A., ALBARAKATI, N., BOWELL, L., AGARWAL, D., MOSELEY, P., HAWKES, C., BALL, G., CHAN, S., ELLIS, I.O. and MADHUSUDAN, S., 2013. Single-strand selective monofunctional uracil-DNA glycosylase (SMUG1) deficiency is linked to aggressive breast cancer and predicts response to adjuvant therapy. Breast Cancer Research and Treatment, 142 (3), pp. 515-527. ISSN 0167-6806

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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 1165 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.

Item Type: Journal article
Publication Title: Breast Cancer Research and Treatment
Creators: Abdel-Fatah, T.M.A., Albarakati, N., Bowell, L., Agarwal, D., Moseley, P., Hawkes, C., Ball, G., Chan, S., Ellis, I.O. and Madhusudan, S.
Publisher: Springer
Date: 2013
Volume: 142
Number: 3
ISSN: 0167-6806
Identifiers:
NumberType
10.1007/s10549-013-2769-6DOI
Divisions: Schools > School of Science and Technology
Depositing User: EPrints Services
Date Added: 09 Oct 2015 09:55
Last Modified: 09 Jun 2017 13:14
URI: http://irep.ntu.ac.uk/id/eprint/4955

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