Table_2_Breast Cancer Subtypes Present a Differential Production of Reactive Oxygen Species (ROS) and Susceptibility to Antioxidant Treatment.XLSX

Due to their crucial role in cell metabolism and homeostasis, alterations in mitochondrial biology and function have been related to the progression of diverse diseases including cancer. One of the consequences associated to mitochondrial dysfunction is the production of reactive oxygen species (ROS). ROS are known to have a controversial role during cancer initiation and progression and although several studies have tried to manipulate intracellular ROS levels using antioxidants or pro-oxidation conditions, it is not yet clear how to target oxidation for cancer therapy. In this study, we found differences in mitochondrial morphology in breast cancer cells when compared to a non-tumorigenic cell line and differences in mitochondrial function among breast cancer subtypes when exploring gene-expression data from the TCGA tumor dataset. Interestingly, we found increased ROS levels in triple negative breast cancer (TNBC) cell lines and a dependency on ROS for survival since antioxidant treatment induced cell death in TNBC cells but not in an estrogen receptor positive (ER+) cell line. Moreover, we identified the mitochondria as the main source of ROS in TNBC cell lines. Our results indicate a potential use for ROS as a target for therapy in the TNBC subtype which currently has the worst prognosis among all breast cancers and remains as the only breast cancer subtype which lacks a targeted therapy.

鉴于线粒体生物学与功能在细胞代谢和稳态中扮演的关键角色，线粒体生物学与功能的改变与多种疾病的进展，包括癌症，密切相关。与线粒体功能障碍相关的一种后果是活性氧（ROS）的产生。活性氧在癌症的发生和进展过程中扮演着复杂的角色，尽管已有数项研究尝试通过抗氧化剂或促氧化条件来操控细胞内ROS水平，但如何针对氧化进行癌症治疗仍尚无定论。在本研究中，我们通过对比肿瘤基因组学联盟（TCGA）肿瘤数据集中的基因表达数据，发现乳腺癌细胞与无肿瘤转化细胞系相比，存在线粒体形态的差异，以及不同乳腺癌亚型之间存在线粒体功能的差异。有趣的是，我们发现三阴性乳腺癌（TNBC）细胞系中ROS水平升高，且对ROS的依赖性是生存的关键，因为抗氧化治疗可诱导TNBC细胞的死亡，而对雌激素受体阳性（ER+）细胞系则无此效应。此外，我们确定线粒体是TNBC细胞系中ROS的主要来源。我们的研究结果表明，ROS作为治疗TNBC亚型的潜在靶点具有应用价值，TNBC亚型是目前所有乳腺癌中预后最差的，并且是唯一缺乏靶向治疗的乳腺癌亚型。