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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.
Introduction
Patients suffering from cancer often experience a variety of chronic emotional stressors (1), including depression, anxiety, and fear (2, 3). These serve as risk factors by facilitating tumor growth and increasing expression of invasion-related genes that promote cancer progression (4). Indeed, chronic stress increases catecholamine levels and promotes tumor burden and invasive growth of ovarian carcinoma cells in vivo (5). Moreover, stressinduced hormones have been shown to increase cancer cell dissemination in pancreatic cancer (4). Immune activity has long been established as being suppressed by chronic stress and is considered to be responsible for promoting cancer (6, 7). Yet, the direct signaling network between stress pathways and a cancer-propagating program remains almost completely unknown.
Cancer stem-like cells (CSCs) are characterized by an increased capability of self-renewal (8) and tumor reconstitution (9). They are able to generate heterogeneous lineages of cancer cells that constitute tumors. These CSCs are important for the initiation, maintenance, and clinical outcome of many cancers. Previous studies have demonstrated that transcription factors such as MYC, SLUG, and SOX2 are responsible for tumorigenesis and can reprogram cells from a differentiated to a stem-like state in a variety of cancers (10-12). Indeed, the transcription factor MYC plays key roles in oncogenesis and is involved in many cancer networks (13). MYC increases SOX2 transcriptional activity, forming a positive-feedback loop involving the Wnt/ß-catenin/MYC/ SOX2 axis, which defines a highly tumorigenic cell subpopulation in ALK-positive anaplastic large cell lymphomas (14). Moreover, SOX2 represses microRNA-452 (miR-452), which acts as a metastasis...