Department of Genetics, Cell Biology and Anatomy, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska.
Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska.
Mol Cancer Res. 2022 Sep 2;20(9):1391-1404. doi: 10.1158/1541-7786.MCR-22-0122.
Ecdysoneless (ECD) protein is essential for embryogenesis, cell-cycle progression, and cellular stress mitigation with an emerging role in mRNA biogenesis. We have previously shown that ECD protein as well as its mRNA are overexpressed in breast cancer and ECD overexpression predicts shorter survival in patients with breast cancer. However, the genetic evidence for an oncogenic role of ECD has not been established. Here, we generated transgenic mice with mammary epithelium-targeted overexpression of an inducible human ECD transgene (ECDTg). Significantly, ECDTg mice develop mammary hyperplasia, preneoplastic lesions, and heterogeneous tumors with occasional lung metastasis. ECDTg tumors exhibit epithelial to mesenchymal transition and cancer stem cell characteristics. Organoid cultures of ECDTg tumors showed ECD dependency for in vitro oncogenic phenotype and in vivo growth when implanted in mice. RNA sequencing (RNA-seq) analysis of ECDTg tumors showed a c-MYC signature, and alterations in ECD levels regulated c-MYC mRNA and protein levels as well as glucose metabolism. ECD knockdown-induced decrease in glucose uptake was rescued by overexpression of mouse ECD as well as c-MYC. Publicly available expression data analyses showed a significant correlation of ECD and c-MYC overexpression in breast cancer, and ECD and c-MYC coexpression exhibits worse survival in patients with breast cancer. Taken together, we establish a novel role of overexpressed ECD as an oncogenesis driver in the mouse mammary gland through upregulation of c-MYC-mediated glucose metabolism.
We demonstrate ECD overexpression in the mammary gland of mice led to the development of a tumor progression model through upregulation of c-MYC signaling and glucose metabolism.
ecdysoneless (ECD) 蛋白对于胚胎发生、细胞周期进程和细胞应激缓解至关重要，并且在 mRNA 生物发生中发挥着新兴作用。我们之前已经表明，ECD 蛋白及其 mRNA 在乳腺癌中过度表达，ECD 过表达预示着乳腺癌患者的生存时间更短。然而，ECD 的致癌作用的遗传证据尚未建立。在这里，我们生成了具有乳腺上皮细胞靶向过表达诱导型人 ECD 转基因 (ECDTg) 的转基因小鼠。重要的是，ECD 小鼠发展为乳腺增生、癌前病变和异质性肿瘤，偶尔发生肺转移。ECD 小鼠肿瘤表现出上皮到间充质转化和癌症干细胞特征。ECD 小鼠肿瘤的类器官培养显示 ECDTg 肿瘤在体外具有致癌表型和体内生长依赖于 ECD，当植入小鼠时。ECD 小鼠肿瘤的 RNA 测序 (RNA-seq) 分析显示 c-MYC 特征，并且 ECD 水平的改变调节 c-MYC mRNA 和蛋白水平以及葡萄糖代谢。ECD 敲低诱导的葡萄糖摄取减少可通过过表达小鼠 ECD 以及 c-MYC 得到挽救。公开可用的表达数据分析表明，乳腺癌中 ECD 和 c-MYC 过表达存在显著相关性，并且 ECD 和 c-MYC 共表达在乳腺癌患者中表现出更差的生存。总之，我们通过上调 c-MYC 信号和葡萄糖代谢，在小鼠乳腺中建立了过表达 ECD 作为致癌驱动因素的新作用。
我们证明了在小鼠乳腺中过表达 ECD 通过上调 c-MYC 信号和葡萄糖代谢导致肿瘤进展模型的发展。
