PDF(Pubmed)
Abstract：
Triple-negative breast cancer (TNBC) is characterized by the absence of the estrogen receptor, progesterone receptor, and receptor tyrosine kinase HER2 expression. Due to the limited number of FDA-approved targeted therapies for TNBC, there is an ongoing need to understand the molecular underpinnings of TNBC for the development of novel combinatorial treatment strategies. This study evaluated the role of the MerTK receptor tyrosine kinase on proliferation and invasion/metastatic potential in TNBC. Immunohistochemical analysis demonstrated MerTK expression in 58% of patient-derived TNBC xenografts. The stable overexpression of MerTK in human TNBC cell lines induced an increase in proliferation rates, robust in vivo tumor growth, heightened migration/invasion potential, and enhanced lung metastases. NanoString nCounter analysis of MerTK-overexpressing SUM102 cells (SUM102-MerTK) revealed upregulation of several signaling pathways, which ultimately drive cell cycle progression, reduce apoptosis, and enhance cell survival. Proteomic profiling indicated increased endoglin (ENG) production in SUM102-MerTK clones, suggesting that MerTK creates a conducive environment for increased proliferative and metastatic activity via elevated ENG expression. To determine ENG\'s role in increasing proliferation and/or metastatic potential, we knocked out ENG in a SUM102-MerTK clone with CRISPR technology. Although this ENG knockout clone exhibited similar in vivo growth to the parental SUM102-MerTK clone, lung metastasis numbers were significantly decreased ~4-fold, indicating that MerTK enhances invasion and metastasis through ENG. Our data suggest that MerTK regulates a unique proliferative signature in TNBC, promoting robust tumor growth and increased metastatic potential through ENG upregulation. Targeting MerTK and ENG simultaneously may provide a novel therapeutic approach for TNBC patients.
摘要：
三阴性乳腺癌（TNBC）的特征是缺乏雌激素受体，孕激素受体,和受体酪氨酸激酶HER2表达。由于FDA批准的TNBC靶向治疗的数量有限，为了开发新的组合治疗策略,需要了解TNBC的分子基础.这项研究评估了MerTK受体酪氨酸激酶对TNBC增殖和侵袭/转移潜力的作用。免疫组织化学分析显示MerTK在58%的患者来源的TNBC异种移植物中表达。MerTK在人TNBC细胞系中的稳定过表达诱导增殖率增加,体内肿瘤生长强劲，增加的迁移/入侵潜力，和增强的肺转移。对MerTK过表达的SUM102细胞（SUM102-MerTK）的NanoStringnCounter分析揭示了几种信号通路的上调，最终推动细胞周期进程，减少凋亡，增强细胞存活。蛋白质组分析表明SUM102-MerTK克隆中的内皮糖蛋白（ENG）产量增加，表明MerTK通过升高的ENG表达为增加的增殖和转移活性创造了有利的环境。为了确定ENG在增加增殖和/或转移潜能中的作用，我们用CRISPR技术在SUM102-MerTK克隆中敲除了ENG。尽管该ENG敲除克隆显示出与亲本SUM102-MerTK克隆相似的体内生长，肺转移数量显著减少~4倍，表明MerTK通过ENG增强侵袭和转移。我们的数据表明，MerTK调节TNBC中独特的增殖特征，通过ENG上调促进肿瘤生长和增加转移潜力。同时靶向MerTK和ENG可能为TNBC患者提供一种新的治疗方法。
