BRCA1 Induces Major Energetic Metabolism Reprogramming in Breast Cancer Cells

The hypermetabolic nature of cancer cells and their increased reliance on “aerobic glycolysis”, as originally described by Otto Warburg and colleagues, are considered metabolic hallmarks of cancer cells. BRCA1 is a major tumor suppressor in breast cancer and it was implicated in numerous pathways resulting in anticarcinogenic functions. The objective of our study was to address specific contributions of BRCA1 to the metabolic features of cancer cells, including the so-called “Warburg effect”. To get a comprehensive approach of the role of BRCA1 in tumor cell metabolism, we performed a global transcriptional and metabolite profiling in a BRCA1-mutated breast cancer cell line transfected or not by wild-type BRCA1. This study revealed that BRCA1 induced numerous modifications of metabolism, including strong inhibition of glycolysis while TCA cycle and oxidative phosphorylation tended to be activated. Regulation of AKT by BRCA1 in both our cell model and BRCA1-mutated breast tumors was suggested to participate in the effect of BRCA1 on glycolysis. We could also show that BRCA1 induced a decrease of ketone bodies and free fatty acids, maybe consumed to supply Acetyl-CoA for TCA cycle. Finally increased activity of antioxidation pathways was observed in BRCA1-transfected cells, that could be a consequence of ROS production by activated oxidative phosphorylation. Our study suggests a new function for BRCA1 in cell metabolic regulation, globally resulting in reversion of the Warburg effect. This could represent a new mechanism by which BRCA1 may exert tumor suppressor function.

癌细胞的高代谢特性及其对“有氧糖酵解(aerobic glycolysis)”的依赖性增强，这一现象最初由奥托·瓦尔堡（Otto Warburg）及其同事所描述，现已被视为癌细胞的代谢标志性特征。BRCA1是乳腺癌中的主要抑癌基因，其参与多条通路并发挥抗癌功能。本研究旨在探究BRCA1对癌细胞代谢特征的具体调控作用，其中包括前述的“瓦博格效应(Warburg effect)”。为全面解析BRCA1在肿瘤细胞代谢中的调控作用，本研究针对转染野生型BRCA1或未转染的BRCA1突变型乳腺癌细胞系，开展了全转录组与代谢组全局分析。本研究结果显示，BRCA1可引发代谢通路的广泛重塑：其显著抑制糖酵解过程，同时可激活三羧酸（TCA）循环与氧化磷酸化(oxidative phosphorylation)通路。研究提示，在本研究的细胞模型以及BRCA1突变型乳腺癌组织中，BRCA1对AKT的调控可能参与了其对糖酵解过程的影响。本研究还证实，BRCA1可降低酮体与游离脂肪酸的水平，这一变化或为三羧酸循环供应乙酰辅酶A(Acetyl-CoA)的代谢消耗所致。最后，在转染BRCA1的细胞中，抗氧化通路的活性显著上调，这可能是活化的氧化磷酸化过程产生活性氧(ROS)所引发的后续效应。本研究表明，BRCA1在细胞代谢调控中存在全新功能，其整体效应可逆转瓦博格效应。这或许是BRCA1发挥抑癌功能的全新分子机制。