Shen Liangliang, O'Shea John M, Kaadige Mohan R, Cunha Stéphanie, Wilde Blake R, Cohen Adam L, Welm Alana L, Ayer Donald E
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.
Departments of Oncological Sciences and Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112-5550.
Proc Natl Acad Sci U S A. 2015 Apr 28;112(17):5425-30. doi: 10.1073/pnas.1501555112. Epub 2015 Apr 13.
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.
三阴性乳腺癌（TNBC）具有侵袭性且缺乏靶向治疗方法。了解TNBC中营养物质的利用方式可能为治疗干预提供新的靶点。我们证明转录因子c-Myc驱动TNBC细胞中的葡萄糖代谢，但通过一种以前未被认识到的机制来实现，该机制涉及直接抑制硫氧还蛋白相互作用蛋白（TXNIP）。TXNIP是葡萄糖摄取、有氧糖酵解和糖酵解基因表达的有效负调节因子；因此，c-Myc对它的抑制为c-Myc驱动的葡萄糖代谢提供了一条替代途径。c-Myc通过结合TXNIP启动子中含E-box的区域来降低TXNIP基因表达，可能与相关转录因子MondoA竞争。TXNIP的抑制增加葡萄糖摄取并导致对糖酵解的依赖。异位表达TXNIP可降低葡萄糖摄取、减少细胞增殖并增加细胞凋亡。支持c-Myc与TXNIP之间相互关系的生物学意义的是，Myc高/TXNIP低基因特征与乳腺癌患者总生存期降低和无转移生存期降低相关。Myc高/TXNIP低基因特征与不良临床结局之间的相关性仅在TNBC中明显，在其他乳腺癌亚型中则不明显。TP53突变是TNBC的一个决定性分子特征，它增强了Myc高/TXNIP低基因特征与乳腺癌死亡之间的相关性。由于Myc驱动营养物质利用而TXNIP限制葡萄糖可用性，我们提出Myc高/TXNIP低基因特征将营养物质利用与营养物质可用性协调起来。此外，我们的数据表明p53肿瘤抑制因子的缺失与Myc高/TXNIP低驱动的代谢失调协同作用，驱动TNBC的侵袭性临床行为。
