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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Published in The Journal of Clinical Investigation, v. 129, no. 3.

This work is licensed under the Creative Commons Attribution 4.0 International License.

The first 20 authors and the author from the University of Kentucky are shown on the author list above. Please refer to the downloaded document for the complete author list.

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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).

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