Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, USA.
Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA.
Oncogene. 2018 Mar;37(10):1308-1325. doi: 10.1038/s41388-017-0023-0. Epub 2017 Dec 18.
In order to better understand the process of breast cancer metastasis, we have generated a mammary epithelial progression series of increasingly aggressive cell lines that metastasize to lung. Here we demonstrate that upregulation of an endoplasmic reticulum (ER) to Golgi trafficking gene signature in metastatic cells enhances transport kinetics, which promotes malignant progression. We observe increased ER-Golgi trafficking, an altered secretome and sensitivity to the retrograde transport inhibitor brefeldin A (BFA) in cells that metastasize to lung. CREB3 was identified as a transcriptional regulator of upregulated ER-Golgi trafficking genes ARF4, COPB1, and USO1, and silencing of these genes attenuated the metastatic phenotype in vitro and lung colonization in vivo. Furthermore, high trafficking gene expression significantly correlated with increased risk of distant metastasis and reduced relapse-free and overall survival in breast cancer patients, suggesting that modulation of ER-Golgi trafficking plays an important role in metastatic progression.
为了更好地理解乳腺癌转移的过程，我们生成了一系列乳腺上皮进展细胞系，这些细胞系越来越具有侵袭性，并转移到肺部。在这里，我们证明转移性细胞中内质网（ER）到高尔基体运输基因特征的上调增强了运输动力学，从而促进了恶性进展。我们观察到转移性细胞中 ER-Golgi 运输增加、分泌组改变以及对逆行运输抑制剂布雷菲德菌素 A（BFA）的敏感性增加。CREB3 被鉴定为上调的 ER-Golgi 运输基因 ARF4、COPB1 和 USO1 的转录调节剂，这些基因的沉默减弱了体外转移表型和体内肺定植。此外，高运输基因表达与乳腺癌患者远处转移风险增加、无复发生存期和总生存期缩短显著相关，表明 ER-Golgi 运输的调节在转移进展中起着重要作用。
