title: Metabolic reprogramming in triple-negative breast cancer through Myc suppression of TXNIP.
abstract: 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.
authors: The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, 710032 China; and Departments of Oncological Sciences and Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112-5550.
authors: Liangliang
authors: L
authors: Shen
authors: Departments of Oncological Sciences and Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112-5550.
authors: John M
authors: JM
authors: O'Shea
authors: Departments of Oncological Sciences and Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112-5550.
authors: Mohan R
authors: MR
authors: Kaadige
authors: Departments of Oncological Sciences and Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112-5550.
authors: Stéphanie
authors: S
authors: Cunha
authors: Departments of Oncological Sciences and Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112-5550.
authors: Blake R
authors: BR
authors: Wilde
authors: Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112-5550 Medicine and.
authors: Adam L
authors: AL
authors: Cohen
authors: Departments of Oncological Sciences and Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112-5550.
authors: Alana L
authors: AL
authors: Welm
authors: Departments of Oncological Sciences and Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112-5550 don.ayer@hci.utah.edu.
authors: Donald E
authors: DE
authors: Ayer
mesh_terms: D017209:Apoptosis / Q000235:genetics; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D065150:Cellular Reprogramming; D005260:Female; D005947:Glucose / Q000235:genetics / Q000378:metabolism; D006019:Glycolysis / Q000235:genetics; D006801:Humans; D009154:Mutation; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D002352:Carrier Proteins; C485496:MLXIP protein, human; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; C495901:TP53 protein, human; C486715:TXNIP protein, human; D016159:Tumor Suppressor Protein p53; D005947:Glucose
keywords: MondoA; Myc; glycolysis; thioredoxin-interacting protein; triple-negative breast cancer