Chronic stress triggers activation of the sympathetic nervous system and drives malignancy. Using an immunodeficient murine system, we showed that chronic stress–induced epinephrine promoted breast cancer stem-like properties via lactate dehydrogenase A–dependent (LDHA-dependent) metabolic rewiring. Chronic stress–induced epinephrine activated LDHA to generate lactate, and the adjusted pH directed USP28-mediated deubiquitination and stabilization of MYC. The SLUG promoter was then activated by MYC, which promoted development of breast cancer stem-like traits. Using a drug screen that targeted LDHA, we found that a chronic stress–induced cancer stem-like phenotype could be reversed by vitamin C. These findings demonstrated the critical importance of psychological factors in promoting stem-like properties in breast cancer cells. Thus, the LDHA-lowering agent vitamin C can be a potential approach for combating stress-associated breast cancer.
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This research work was supported by the National Natural Science Foundation of China (81820108024 to QL;81630005 to QL; 81573025 to QL; and 81703091 to FA); the Science and Technology Planning Project of Guangzhou (201604020163 to QL); and the Dalian High-level Talent Innovation Program (2016RD12 to QL). EWFL’s work is supported by the Medical Research Council (MRC) (MR/N012097/1); Cancer Research UK (CRUK) (C37/A12011; C37/A18784); Breast Cancer Now (2012MayPR070; 2012NovPhD016); the CRUK Imperial Centre, Imperial Experimental Cancer Medicine Centre (ECMC); and the National Institute for Health Research (NIHR) Imperial Biomedical Research Centre (BRC).
Cui, Bai; Luo, Yuanyuan; Tian, Pengfei; Peng, Fei; Lu, Jinxin; Yang, Yongliang; Su, Qitong; Liu, Bing; Yu, Jiachuan; Luo, Xi; Yin, Liu; Cheng, Wei; An, Fan; He, Bin; Liang, Dapeng; Wu, Sijin; Chu, Peng; Song, Luyao; Liu, Xinyu; Luo, Huandong; and Zhou, Binhua P., "Stress-Induced Epinephrine Enhances Lactate Dehydrogenase A and Promotes Breast Cancer Stem-Like Cells" (2019). Molecular and Cellular Biochemistry Faculty Publications. 190.