期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：17
页码：5425-5430
DOI：10.1073/pnas.1501555112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceTriple-negative breast cancers (TNBCs) are aggressive with poor clinical outcomes. Understanding the pathways that control their aggressive growth may reveal new targets for therapeutic intervention. TNBCs are highly glycolytic, providing fuel for growth promoting biosynthetic pathways. We establish that the c-Myc transcription factor drives this metabolic phenotype. Classically, the c-Myc proto-oncogene drives glycolysis by activating target genes encoding glycolytic enzymes and glucose transporters; however, we show here that c-Myc represses the expression of thioredoxin-interacting protein (TXNIP), which is a potent blocker of glucose utilization. Thus, c-Myc's repression of TXNIP provides an additional route to c-Myc-driven glucose metabolism. Highlighting the clinical significance of our finding, a Mychigh/TXNIPlow gene signature correlates with poor overall survival in TNBC but not in other subclasses of breast cancer. Triple-negative breast cancers (TNBCs) are aggressive and lack targeted therapies. Understanding how nutrients are used in TNBCs may provide new targets for therapeutic intervention. We demonstrate that the transcription factor c-Myc drives glucose metabolism in TNBC cells but does so by a previously unappreciated mechanism that involves direct repression of thioredoxin-interacting protein (TXNIP). TXNIP is a potent negative regulator of glucose uptake, aerobic glycolysis, and glycolytic gene expression; thus its repression by c-Myc provides an alternate route to c-Myc-driven glucose metabolism. c-Myc reduces TXNIP gene expression by binding to an E-box-containing region in the TXNIP promoter, possibly competing with the related transcription factor MondoA. TXNIP suppression increases glucose uptake and drives a dependence on glycolysis. Ectopic TXNIP expression decreases glucose uptake, reduces cell proliferation, and increases apoptosis. Supporting the biological significance of the reciprocal relationship between c-Myc and TXNIP, a Mychigh/TXNIPlow gene signature correlates with decreased overall survival and decreased metastasis-free survival in breast cancer. The correlation between the Mychigh/TXNIPlow gene signature and poor clinical outcome is evident only in TNBC, not in other breast cancer subclasses. Mutation of TP53, which is a defining molecular feature of TNBC, enhances the correlation between the Mychigh/TXNIPlow gene signature and death from breast cancer. Because Myc drives nutrient utilization and TXNIP restricts glucose availability, we propose that the Mychigh/TXNIPlow gene signature coordinates nutrient utilization with nutrient availability. Further, our data suggest that loss of the p53 tumor suppressor cooperates with Mychigh/TXNIPlow-driven metabolic dysregulation to drive the aggressive clinical behavior of TNBC.
关键词：Myc ; MondoA ; thioredoxin-interacting protein ; glycolysis ; triple-negative breast cancer
