Department of Medical Biology, Faculty of Health Sciences, UiT - The Arctic University of Norway, 9037, Tromsö, Norway.
Institute of Biophysics, Biological Research Centre, Hungarian Academy of Sciences, Szeged, Hungary.
Sci Rep. 2020 Jul 22;10(1):12237. doi: 10.1038/s41598-020-69242-1.
This study demonstrates a role for the extracellular matrix protein nephronectin (NPNT) in promoting experimental breast cancer brain metastasis, possibly through enhanced binding to- and migration through brain endothelial cells. With the introduction of more targeted breast cancer treatments, a prolonged survival has resulted during the last decade. Consequently, an increased number of patients develop metastasis in the brain, a challenging organ to treat. We recently reported that NPNT was highly expressed in primary breast cancer and associated with unfavourable prognosis. The current study addresses our hypothesis that NPNT promotes brain metastases through its integrin-binding motifs. SAGE-sequencing revealed that NPNT was significantly up-regulated in human breast cancer tissue compared to pair-matched normal breast tissue. Human brain metastatic breast cancers expressed both NPNT and its receptor, integrin α8β1. Using an open access repository; BreastMark, we found a correlation between high NPNT mRNA levels and poor prognosis for patients with the luminal B subtype. The 66cl4 mouse cell line was used for expression of wild-type and mutant NPNT, which is unable to bind α8β1. Using an in vivo model of brain metastatic colonization, 66cl4-NPNT cells showed an increased ability to form metastatic lesions compared to cells with mutant NPNT, possibly through reduced endothelial adhesion and transmigration.
本研究表明细胞外基质蛋白nephronectin（NPNT）在促进实验性乳腺癌脑转移中起作用，可能通过增强与脑内皮细胞的结合和迁移来实现。在过去十年中，随着更具针对性的乳腺癌治疗方法的引入，患者的生存时间延长。因此，越来越多的患者在大脑中出现转移，这是一个具有挑战性的治疗器官。我们最近报道 NPNT 在原发性乳腺癌中高度表达，并与不良预后相关。本研究旨在验证我们的假设，即 NPNT 通过其整合素结合基序促进脑转移。SAGE 测序显示，与配对的正常乳腺组织相比，NPNT 在人类乳腺癌组织中显著上调。人脑转移性乳腺癌表达 NPNT 及其受体整合素 α8β1。通过使用开放获取资源库；BreastMark，我们发现高 NPNT mRNA 水平与 luminal B 亚型患者的预后不良相关。66cl4 小鼠细胞系用于表达野生型和不能与 α8β1 结合的突变型 NPNT。在脑转移定植的体内模型中，与携带突变 NPNT 的细胞相比，66cl4-NPNT 细胞形成转移性病变的能力增强，可能是通过减少内皮细胞黏附和迁移来实现的。
