Ning Lvwen, Xie Ni
Biobank, Shenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen University, Shenzhen, People's Republic of China.
Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, People's Republic of China.
Cancer Manag Res. 2024 Mar 8;16:137-150. doi: 10.2147/CMAR.S445248. eCollection 2024.
The Sirtuin (SIRT) family consists of seven evolutionary conserved NAD-dependent deacetylases that play important roles in various cancers, including breast cancer (BC). SIRTs expression has been reported to have prognostic value in BC, but these studies used limited sample size and yielded inconsistent conclusions. This study evaluated the association of SIRT3 and other SIRT family members with survival and neoadjuvant chemotherapy outcomes.
BC patients' data was obtained from the TCGA-BRCA, METABRIC and GEO databases, comprising 4336 samples. SIRTs expression and overall survival (OS) were analyzed using Kaplan-Meier analysis and Cox proportional hazards regression. SIRT3 expression levels were compared between pathologic complete response (pCR) and non-pCR groups after neoadjuvant chemotherapy in triple-negative breast cancer (TNBC). Protein-protein interaction networks were constructed using the STRING database. Gene set enrichment analysis (GSEA) was performed to explore potential functions of SIRT3.
Through systematic analysis of SIRTs expression and OS of BC using three independent cohorts: TCGA-BRCA, METABRIC and GSE16446, we found that high SIRT3 expression was significantly associated with worse OS in TNBC in the TCGA-BRCA cohort, which was validated in the METABRIC and GSE16446 cohorts. SIRT3 expression was correlated with BC subtypes and American Joint Committee on Cancer (AJCC) T stage, but not with age-at-diagnosis, race, or tumor stage. Moreover, TNBC patients with higher SIRT3 expression had lower pCR rates after neoadjuvant chemotherapy (p = 6.40e-03) and SIRT3 expression was significantly lower in the pCR group than in the non-pCR group in TNBC (p = 4.2e-03). GSEA indicated that SIRT3 was involved in drug-related pathways such as oxidative phosphorylation, metabolism of xenobiotics by cytochrome P450, and drug metabolism.
Our study suggests that SIRT3 is a potential biomarker for both OS and neoadjuvant chemosensitivity in TNBC. It may also assist in selecting suitable candidates and treatment options for TNBC patients.
沉默调节蛋白（SIRT）家族由七种进化保守的NAD依赖性脱乙酰酶组成，它们在包括乳腺癌（BC）在内的各种癌症中发挥重要作用。据报道，SIRTs表达在BC中具有预后价值，但这些研究样本量有限，结论不一致。本研究评估了SIRT3和其他SIRT家族成员与生存及新辅助化疗结果的关联。
从TCGA-BRCA、METABRIC和GEO数据库获取BC患者数据，共4336个样本。使用Kaplan-Meier分析和Cox比例风险回归分析SIRTs表达和总生存期（OS）。在三阴性乳腺癌（TNBC）新辅助化疗后的病理完全缓解（pCR）组和非pCR组之间比较SIRT3表达水平。使用STRING数据库构建蛋白质-蛋白质相互作用网络。进行基因集富集分析（GSEA）以探索SIRT3的潜在功能。
通过对TCGA-BRCA、METABRIC和GSE16446这三个独立队列中BC的SIRTs表达和OS进行系统分析，我们发现，在TCGA-BRCA队列中，高SIRT3表达与TNBC患者较差的OS显著相关，这在METABRIC和GSE16446队列中得到验证。SIRT3表达与BC亚型和美国癌症联合委员会（AJCC）T分期相关，但与诊断时年龄、种族或肿瘤分期无关。此外，SIRT3表达较高的TNBC患者新辅助化疗后的pCR率较低（p = 6.40e-03），且在TNBC中，pCR组的SIRT3表达明显低于非pCR组（p = 4.2e-03）。GSEA表明，SIRT3参与氧化磷酸化、细胞色素P450对外源化学物质的代谢以及药物代谢等与药物相关的途径。
我们的研究表明，SIRT3是TNBC患者OS和新辅助化疗敏感性的潜在生物标志物。它还可能有助于为TNBC患者选择合适的候选者和治疗方案。
