Table_1_Breast Cancer Subtypes Present a Differential Production of Reactive Oxygen Species (ROS) and Susceptibility to Antioxidant Treatment.DOCX

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及稳态维持中的关键作用，线粒体生物学与功能的改变与包括癌症在内的多种疾病的发生发展密切相关。线粒体功能障碍所伴随的后果之一即为活性氧（ROS）的产生。活性氧在癌症的起始与发展过程中扮演着复杂且具有争议的角色；尽管多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，然而，针对氧化反应在癌症治疗中的应用策略尚不明确。在本研究中，我们通过对比乳腺癌细胞与未肿瘤化细胞系，以及分析TCGA肿瘤数据集中基因表达数据，发现乳腺癌亚型之间线粒体形态及功能的差异。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ROS对TNBC细胞的生存至关重要，因为抗氧化治疗可诱导TNBC细胞死亡，而对雌激素受体阳性（ER+）细胞系则无此效应。此外，我们确定了线粒体是TNBC细胞系中ROS的主要来源。我们的研究结果提示，ROS可作为TNBC亚型治疗靶点，而TNBC亚型是目前所有乳腺癌亚型中预后最差的，并且是唯一缺乏靶向治疗方案的乳腺癌亚型。