Department of Oncology, Nottingham University Hospitals, Nottingham, NG51PB, UK.
Breast Cancer Res Treat. 2013 Dec;142(3):515-27. doi: 10.1007/s10549-013-2769-6. Epub 2013 Nov 20.
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.
尿嘧啶是 DNA 中的一种重要诱变剂。SMUG1 是一种尿嘧啶-DNA 糖基化酶，通过碱基切除修复去除尿嘧啶。SMUG1 还能处理放射诱导的氧化碱基损伤以及化疗过程中 5-氟尿嘧啶掺入 DNA。我们研究了 249 例原发性乳腺癌中的 SMUG1 mRNA 表达。在 1165 例随机分为两个队列的乳腺癌肿瘤中[训练集（n=583）和测试集（n=582）]研究了 SMUG1 蛋白表达。在一系列 315 例 ER 阴性肿瘤（n=315）中还研究了 SMUG1 和化疗反应。为了深入了解机制，将 SMUG1 与侵袭性表型、DNA 修复、细胞周期和细胞凋亡的生物标志物相关联。低 SMUG1 mRNA 表达与不良疾病特异性生存率（p=0.008）和无病生存率（p=0.008）相关。低 SMUG1 蛋白表达（25%）与高组织学分级（p<0.0001）、高有丝分裂指数（p<0.0001）、多形性（p<0.0001）、腺体去分化（p=0.0001）、缺乏激素受体（ER-/PgR-/AR）（p<0.0001）、基底样（p<0.0001）和三阴性表型（p<0.0001）相关。低 SMUG1 蛋白表达与 BRCA1（p<0.0001）、ATM（p<0.0001）和 XRCC1（p<0.0001）的缺失相关。低 p27（p<0.0001）、低 p21（p=0.023）、突变型 p53（p=0.037）、低 MDM2（p<0.0001）、低 MDM4（p=0.004）、低 Bcl-2（p=0.001）、低 Bax（p=0.003）和高 MIB1（p<0.0001）在低 SMUG1 肿瘤中可能存在。低 SMUG1 蛋白表达与单变量分析（p<0.001）和多变量分析（p<0.01）中的不良预后相关。在接受辅助内分泌治疗的 ER+队列中，低 SMUG1 蛋白表达仍与不良生存相关（p<0.01）。在接受辅助化疗的 ER-队列中，低 SMUG1 蛋白表达与生存改善相关（p=0.043）。我们的研究表明，低 SMUG1 表达可能与不良临床病理特征相关，并可预测乳腺癌对辅助治疗的反应。
