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Stress-induced epinephrine enhances lactate dehydrogenase A and promotes breast cancer stem-like cells.

ABSTRACT: 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.

SUBMITTER: Cui B

PROVIDER: S-EPMC6391112 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Stress-induced epinephrine enhances lactate dehydrogenase A and promotes breast cancer stem-like cells.

Cui Bai B Luo Yuanyuan Y Tian Pengfei P Peng Fei F Lu Jinxin J Yang Yongliang Y Su Qitong Q Liu Bing B Yu Jiachuan J Luo Xi X Yin Liu L Cheng Wei W An Fan F He Bin B Liang Dapeng D Wu Sijin S Chu Peng P Song Luyao L Liu Xinyu X Luo Huandong H Xu Jie J Pan Yujia Y Wang Yang Y Li Dangsheng D Huang Peng P Yang Qingkai Q Zhang Lingqiang L Zhou Binhua P BP Liu Suling S Xu Guowang G Lam Eric W-F EW Kelley Keith W KW Liu Quentin Q

The Journal of clinical investigation 20190128 3

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 M ...[more]

PMID: 30688660

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Project description:Obesity is a risk factor for triple-negative breast cancer (TNBC) incidence and poor outcomes, but the underlying molecular biology remains unknown. We previously identified in TNBC cell cultures that expression of epigenetic reader methyl-CpG-binding domain protein 2 (MBD2), specifically the alternative mRNA splicing variant MBD variant 2 (MBD2_v2), is dependent on reactive oxygen species (ROS) and is crucial for maintenance and expansion of cancer stem cell-like cells (CSCs). Because obesity is coupled with inflammation and ROS, we hypothesized that obesity can fuel an increase in MBD2_v2 expression to promote the tumor-initiating CSC phenotype in TNBC cells in vivo. Analysis of TNBC patient datasets revealed associations between high tumor MBD2_v2 expression and high relapse rates and high body mass index (BMI). Stable gene knockdown/overexpression methods were applied to TNBC cell lines to elucidate that MBD2_v2 expression is governed by ROS-dependent expression of serine- and arginine-rich splicing factor 2 (SRSF2). We employed a diet-induced obesity (DIO) mouse model that mimics human obesity to investigate whether obesity causes increased MBD2_v2 expression and increased tumor initiation capacity in inoculated TNBC cell lines. MBD2_v2 and SRSF2 levels were increased in TNBC cell line-derived tumors that formed more frequently in DIO mice relative to tumors in lean control mice. Stable MBD2_v2 overexpression increased the CSC fraction in culture and increased TNBC cell line tumor initiation capacity in vivo. SRSF2 knockdown resulted in decreased MBD2_v2 expression, decreased CSCs in TNBC cell cultures, and hindered tumor formation in vivo. This report describes evidence to support the conclusion that MBD2_v2 expression is induced by obesity and drives TNBC cell tumorigenicity, and thus provides molecular insights into support of the epidemiological evidence that obesity is a risk factor for TNBC. The majority of TNBC patients are obese and rising obesity rates threaten to further increase the burden of obesity-linked cancers, which reinforces the relevance of this report.

Dataset Information

Stress-induced epinephrine enhances lactate dehydrogenase A and promotes breast cancer stem-like cells.

Publications

Stress-induced epinephrine enhances lactate dehydrogenase A and promotes breast cancer stem-like cells.

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