Background: 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.
Methods: 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.
Results: 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.
Conclusion: 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.



中文翻译：

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SIRT3 表达可预测三阴性乳腺癌的总体生存率和新辅助化疗敏感性

背景： Sirtuin (SIRT) 家族由七种进化保守的 NAD 依赖性脱乙酰酶组成，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，但这些研究使用的样本量有限，得出的结论不一致。本研究评估了 SIRT3 和其他 SIRT 家族成员与生存和新辅助化疗结果的关联。
方法： BC患者数据来自TCGA-BRCA、METABRIC和GEO数据库，包含433​​6个样本。使用 Kaplan-Meier 分析和 Cox 比例风险回归分析 SIRT 表达和总生存期 (OS)。比较三阴性乳腺癌（TNBC）新辅助化疗后病理完全缓解（pCR）组和非 pCR 组之间的 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。
结果：通过使用三个独立队列（TCGA-BRCA、METABRIC 和 GSE16446）对 BC 的 SIRT 表达和 OS 进行系统分析，我们发现 SIRT3 高表达与 TCGA-BRCA 队列中 TNBC 较差的 OS 显着相关，这一点在METABRIC 和 GSE16446 队列。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pCR率较低(p = 6.40e-03)，且TNBC中pCR组SIRT3表达显着低于非pCR组(p = 4.2e-03) 。GSEA表明SIRT3参与药物相关途径，如氧化磷酸化、细胞色素P450对异生物质的代谢以及药物代谢。
结论：我们的研究表明 SIRT3 是 TNBC 中 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人和治疗方案。