Xiao Limei, Zhou Jie, Liu Hongyi, Zhou Yuanyuan, Chen Weibin, Cui Wugeng, Zhao Yilin
School of Medicine, Xiamen University, Xiamen, China.
Department of Oncology, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China.
Front Oncol. 2021 Aug 26;11:679262. doi: 10.3389/fonc.2021.679262. eCollection 2021.
There is an urgent need to improve our understanding of breast cancer brain metastases (BCBMs). Thus, we obtained transcriptome data of BCBMs, primary breast cancers (BCs), and extracranial metastases (BCEMs) from the Gene Expression Omnibus (GEO) database, including GSE43837, GSE14017, and GSE14018, for immune and metabolic analysis. Firstly, we performed immune and metabolic analysis on BCBMs and primary breast cancers of GSE43837 using RNA sequence. We identified significant immunosuppression and gene signatures associated with immune infiltration in BCBMs; the lower the expression of the signatures, the worse the prognosis of breast cancer patients in the Kaplan-Meier (KM) plotter [Breast cancer] database. We also identified increased oxidative phosphorylation (OXPHOS) utilization in BCBMs compared with BCs and gene signatures associated with increased OXPHOS utilization in BCBMs; the higher the expression of the signatures, the worse the prognosis of breast cancer patients in the KM plotter [Breast cancer] database, which can predict the prognosis of breast cancer patients better, as it can also predict the prognosis of patients with different breast cancer subtypes. In addition, we performed immune and metabolic analysis on BCBMs and extracranial metastases of GSE14017 and GSE14018 using RNA sequence. Compared with extracranial metastases, we identified more significant immunosuppression but no difference in OXPHOS utilization in BCBMs, which may be because OXPHOS was also involved in extracranial metastases. We have proven that OXPHOS was functionally significant in metastasis assays. Oligomycin, an OXPHOS inhibitor, substantially attenuated the migration and invasion potential of breast cancer cells. Our study provides new insights into the pathogenesis of BCBMs.
Our study reports the most comprehensive gene expression analysis of BCBMs, BCs and extracranial metastases to date. We identified immunosuppression and OXPHOS enrichment in BCBMs compared with BCs, which provide new insights into the pathogenesis of BCBMs and will facilitate the development of new therapeutic strategies for patients with BCBMs.
迫切需要提高我们对乳腺癌脑转移（BCBM）的认识。因此，我们从基因表达综合数据库（GEO）中获取了BCBM、原发性乳腺癌（BC）和颅外转移灶（BCEM）的转录组数据，包括GSE43837、GSE14017和GSE14018，用于免疫和代谢分析。首先，我们使用RNA序列对GSE43837的BCBM和原发性乳腺癌进行了免疫和代谢分析。我们在BCBM中鉴定出了显著的免疫抑制和与免疫浸润相关的基因特征；在Kaplan-Meier（KM）绘图仪[乳腺癌]数据库中，这些特征的表达越低，乳腺癌患者的预后越差。我们还发现，与BC相比，BCBM中氧化磷酸化（OXPHOS）的利用率增加，并且鉴定出了与BCBM中OXPHOS利用率增加相关的基因特征；在KM绘图仪[乳腺癌]数据库中，这些特征的表达越高，乳腺癌患者的预后越差，它可以更好地预测乳腺癌患者的预后，因为它还可以预测不同乳腺癌亚型患者的预后。此外，我们使用RNA序列对GSE1401憨法封盒莩谷凤贪脯楷7和GSE14018的BCBM和颅外转移灶进行了免疫和代谢分析。与颅外转移灶相比，我们在BCBM中鉴定出了更显著的免疫抑制，但OXPHOS利用率没有差异，这可能是因为OXPHOS也参与了颅外转移。我们已经证明OXPHOS在转移实验中具有功能重要性。寡霉素是一种OXPHOS抑制剂，它显著减弱了乳腺癌细胞的迁移和侵袭能力。我们的研究为BCBM的发病机制提供了新的见解。
我们的研究报告了迄今为止对BCBM、BC和颅外转移灶最全面的基因表达分析。我们发现与BC相比，BCBM中存在免疫抑制和OXPHOS富集，这为BCBM的发病机制提供了新的见解，并将促进针对BCBM患者的新治疗策略的开发。
