Esseghir Selma, Kennedy Alan, Seedhar Pooja, Nerurkar Ashutosh, Poulsom Richard, Reis-Filho Jorge S, Isacke Clare M
Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK.
Clin Cancer Res. 2007 Jun 1;13(11):3164-73. doi: 10.1158/1078-0432.CCR-07-0224.
In a previous screen using a signal-trap library, we identified a number of secreted proteins up-regulated in primary tumor cells isolated from invasive breast cancers. The purpose of this study was to assess the expression of these genes in human invasive breast tumors and to determine the significance of their expression for prognosis in breast cancer.
A tissue microarray containing 245 invasive breast tumors from women treated with curative surgery followed by anthracycline-based chemotherapy and hormone therapy for the estrogen receptor (ER)-positive tumors was screened by in situ hybridization with probes against thrombospondin 3 (TSP3), insulin-like growth factor binding protein 7 (IGFBP7), tumor rejection antigen 1 (TRA1), stanniocalcin 2 (STC2), and netrin 4 (NTN4). Correlations between categorical variables were done using the chi(2) test and Fisher's exact test. Cumulative survival probabilities were calculated using the Kaplan-Meier method and multivariate survival analysis was done with Cox hazard model. A series of breast cancers were also stained with NTN4 antibodies.
All five genes examined were expressed in invasive breast tumor cells. NTN4 protein expression was also confirmed by immunohistochemistry. Together, these data validate the design and screening of the signal-trap library. Univariate survival analysis revealed that expressions of TRA1, STC2, and NTN4 are correlated with longer disease-free survival and that TRA1 and NTN4 are associated with longer overall survival. Multivariate analysis showed that NTN4 is an independent prognostic factor of overall survival.
This article describes the identification of three secreted proteins, NTN4, TRA1, and STC2, as potential novel prognostic markers in breast cancer.
在先前使用信号捕获文库进行的筛选中，我们鉴定出一些在从浸润性乳腺癌分离的原发性肿瘤细胞中上调的分泌蛋白。本研究的目的是评估这些基因在人类浸润性乳腺肿瘤中的表达，并确定它们的表达对乳腺癌预后的意义。
通过针对血小板反应蛋白3（TSP3）、胰岛素样生长因子结合蛋白7（IGFBP7）、肿瘤排斥抗原1（TRA1）、鲽钙蛋白2（STC2）和网蛋白4（NTN4）的探针进行原位杂交，对一个组织微阵列进行筛选，该组织微阵列包含245例接受根治性手术治疗，随后对雌激素受体（ER）阳性肿瘤进行蒽环类化疗和激素治疗的女性浸润性乳腺肿瘤。分类变量之间的相关性使用卡方检验和费舍尔精确检验进行分析。使用Kaplan-Meier方法计算累积生存概率，并使用Cox风险模型进行多变量生存分析。还使用NTN4抗体对一系列乳腺癌进行染色。
所检测的所有五个基因均在浸润性乳腺肿瘤细胞中表达。免疫组织化学也证实了NTN4蛋白的表达。这些数据共同验证了信号捕获文库的设计和筛选。单变量生存分析显示，TRA1、STC2和NTN4的表达与更长的无病生存期相关，TRA1和NTN4与更长的总生存期相关。多变量分析表明，NTN4是总生存期的独立预后因素。
本文描述了三种分泌蛋白NTN4、TRA1和STC2作为乳腺癌潜在的新型预后标志物的鉴定。
