Husa Anna-Maria, Magić Željana, Larsson Malin, Fornander Tommy, Pérez-Tenorio Gizeh
Department of Clinical and Experimental Medicine, Division of Oncology, Linköping University, Linköping, Sweden.
Current address: CCRI, Children's Cancer Research Institute, St. Anna Kinderkrebsforschung e.V., Vienna, Austria.
Oncotarget. 2016 Apr 19;7(16):21362-80. doi: 10.18632/oncotarget.7246.
The EPH and ephrins function as both receptor and ligands and the output on their complex signaling is currently investigated in cancer. Previous work shows that some EPH family members have clinical value in breast cancer, suggesting that this family could be a source of novel clinical targets. Here we quantified the mRNA expression levels of EPH receptors and their ligands, ephrins, in 65 node positive breast cancer samples by RT-PCR with TaqMan® Micro Fluidics Cards Microarray. Upon hierarchical clustering of the mRNA expression levels, we identified a subgroup of patients with high expression, and poor clinical outcome. EPHA2, EPHA4, EFNB1, EFNB2, EPHB2 and EPHB6 were significantly correlated with the cluster groups and particularly EPHB2 was an independent prognostic factor in multivariate analysis and in four public databases. The EPHB2 protein expression was also analyzed by immunohistochemistry in paraffin embedded material (cohort 2). EPHB2 was detected in the membrane and cytoplasmic cell compartments and there was an inverse correlation between membranous and cytoplasmic EPHB2. Membranous EPHB2 predicted longer breast cancer survival in both univariate and multivariate analysis while cytoplasmic EPHB2 indicated shorter breast cancer survival in univariate analysis. Concluding: the EPH/EFN cluster analysis revealed that high EPH/EFN mRNA expression is an independent prognostic factor for poor survival. Especially EPHB2 predicted poor breast cancer survival in several materials and EPHB2 protein expression has also prognostic value depending on cell localization.
EPH和ephrin兼具受体和配体的功能，目前正在癌症研究中探究它们复杂信号传导的输出结果。先前的研究表明，一些EPH家族成员在乳腺癌中具有临床价值，这表明该家族可能是新型临床靶点的来源。在这里，我们使用TaqMan®微流体卡微阵列通过逆转录聚合酶链反应（RT-PCR）对65例淋巴结阳性乳腺癌样本中EPH受体及其配体ephrin的mRNA表达水平进行了定量分析。根据mRNA表达水平进行层次聚类分析后，我们确定了一个高表达且临床预后较差的患者亚组。EPHA2、EPHA4、EFNB1、EFNB2、EPHB2和EPHB6与聚类组显著相关，尤其是EPHB2在多变量分析和四个公共数据库中均为独立的预后因素。我们还通过免疫组织化学分析了石蜡包埋材料（队列2）中的EPHB2蛋白表达。在细胞膜和细胞质细胞区室中均检测到了EPHB2，且膜性EPHB2和细胞质EPHB2之间呈负相关。在单变量和多变量分析中，膜性EPHB2均预示着乳腺癌患者的生存期更长，而在单变量分析中，细胞质EPHB2则表明乳腺癌患者的生存期较短。结论：EPH/EFN聚类分析显示，EPH/EFN mRNA高表达是生存期较差的独立预后因素。特别是EPHB2在多种材料中均预示着乳腺癌患者预后较差，并且EPHB2蛋白表达也根据细胞定位具有预后价值。
