Institute of Cancer Sciences, University of Glasgow, Glasgow G11 6NT, UK.
School of Medicine, University of Glasgow, Glasgow Royal Infirmary, Glasgow G4 0SF, UK.
Eur J Cancer. 2014 Jan;50(2):290-301. doi: 10.1016/j.ejca.2013.10.005. Epub 2013 Oct 29.
Sirtuins comprise a family of genes involved in cellular stress, survival and damage responses. They have been implicated in a range of diseases including cancer, with most information pertaining to their function in tumourigenesis being derived from in vitro studies, or model organisms. Their putative roles as tumour suppressors or tumour promoters remain to be validated in vivo. Little is known about their role in breast tumourigenesis. We sought to evaluate the seven sirtuin family members (SIRT1-7) in a human breast cancer cohort, in relation to clinico-pathological features and outcome of the disease.
Immunohistochemical analysis of SIRT1-7 protein levels was undertaken in 392 oestrogen receptor (ER+ve) and 153 ER-ve breast tumour samples. SIRT1-7 transcriptional levels were assessed in normal (n=25), non-malignant (n=73) and malignant (n=70) breast tissue using Relative Quantitative Real Time PCR. Statistical analyses determined if SIRT1-7 transcription or protein expression was associated with clinical parameters or outcome.
In ER-ve tumours, high protein levels of nuclear SIRT2 were associated with reduced time to recurrence and disease-specific death. This association was only observed in Grade 3 tumours. In the ER+ve cohort, high SIRT2 nuclear levels were associated with shorter disease-free survival and time to recurrence whilst on Tamoxifen, in patients with Grade 3 tumours. Conversely, in Grade 2 tumours, high SIRT2 levels were associated with increased time to recurrence.
Our data suggest that SIRT2 is the sirtuin predominantly involved in breast tumourigenesis and prognosis. It indicates that SIRT2 acts as a tumour suppressor or tumour promoter dependent upon breast tumour grade.
沉默调节蛋白构成了一个参与细胞应激、存活和损伤反应的基因家族。它们与包括癌症在内的一系列疾病有关，大多数关于它们在肿瘤发生中的功能的信息都是从体外研究或模型生物中获得的。它们作为肿瘤抑制因子或肿瘤促进因子的潜在作用仍有待在体内验证。关于它们在乳腺癌发生中的作用知之甚少。我们试图在一个人类乳腺癌队列中评估七个沉默调节蛋白家族成员（SIRT1-7），以了解它们与临床病理特征和疾病结局的关系。
对 392 例雌激素受体（ER+ve）和 153 例 ER-ve 乳腺癌样本中的 SIRT1-7 蛋白水平进行免疫组织化学分析。使用相对定量实时 PCR 评估正常（n=25）、非恶性（n=73）和恶性（n=70）乳腺组织中的 SIRT1-7 转录水平。统计分析确定 SIRT1-7 转录或蛋白表达是否与临床参数或结局相关。
在 ER-ve 肿瘤中，核 SIRT2 蛋白水平高与复发时间和疾病特异性死亡时间缩短有关。这种关联仅在 3 级肿瘤中观察到。在 ER+ve 队列中，在接受他莫昔芬治疗的 3 级肿瘤患者中，核 SIRT2 高水平与无病生存期和复发时间缩短有关。相反，在 2 级肿瘤中，SIRT2 高水平与复发时间延长有关。
我们的数据表明，SIRT2 是主要参与乳腺癌发生和预后的沉默调节蛋白。这表明 SIRT2 作为肿瘤抑制因子或肿瘤促进因子的作用取决于乳腺肿瘤的分级。
