High-level JAG1 mRNA and protein predict poor outcome in breast cancer
High-level JAG1 mRNA and protein predict poor outcome in breast cancer
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DOI：
10.1038/modpathol.3800785
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发表时间：
2007-06-01
期刊：
影响因子：
7.5
通讯作者：
Reedijk, Michael
中科院分区：
文献类型：
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作者：
Dickson, Brendan C.;Mulligan, Anna Marie;Reedijk, Michael
Notch受体调节细胞命运决定、干细胞自我更新、增殖和凋亡。我们之前报道Notch配体JAG1 mRNA表达升高可识别预后不良的乳腺癌患者。本研究通过对同一乳腺癌病例（N = 127）的免疫组化分析表明，高表达JAG1蛋白的肿瘤患者的预后比低表达JAG1蛋白的肿瘤患者差（10年生存率为26比48%，中位生存率为63比108个月，P = 0.03）。我们还描述了Allred评分在量化JAG1 mRNA和蛋白表达水平方面的新应用。使用Allred评分，高表达JAG1 mRNA的肿瘤患者的预后比低表达JAG1 mRNA的肿瘤患者差（10年生存率为16% vs 47%，中位生存期为43个月vs 100个月，P < 0.001）。有趣的是，当肿瘤被划分为JAG1 mRNA或蛋白的高表达或低表达时，两种表达分析方法之间只有65%的一致性（kappa = 0.08）。当结合JAG1 mRNA和蛋白数据时，两者表达水平均较低的肿瘤患者的10年生存率为53%，中位生存期为131个月。相比之下，表达高水平JAG1蛋白、mRNA或两者同时表达的肿瘤患者的10年生存率和中位生存率均降低（分别为31%、19%、11%和77、43、23个月，P < 0.0001）。存在交互作用的边缘证据（P = 0.055），表明JAG1蛋白的预后价值仅限于JAG1 mrna低亚组。这些数据表明，Allred评分可用于快速量化乳腺癌中JAG1 mRNA和蛋白水平，以识别具有明显生存劣势的患者，以及可能受益于靶向Notch通路信号传导的治疗（如γ分泌酶抑制剂）的患者。
Notch receptors regulate cell fate determination, stem cell self-renewal, proliferation and apoptosis. We previously reported that elevated mRNA expression of the Notch ligand JAG1 identifies breast cancer patients with a poor prognosis. Here we show through immunohistochemical analysis of the same breast cancer cases (N = 127) that patients with tumors expressing high levels of JAG1 protein had a worse outcome than those with tumors expressing low levels (10-year survival 26 vs 48%, and median survival 63 vs 108 months, respectively; P = 0.03). We also describe the novel application of the Allred score to quantify JAG1 mRNA and protein expression levels. Using the Allred score, patients with tumors expressing high levels of JAG1 mRNA had a worse outcome than those with tumors expressing low levels (10-year survival 16 vs 47%, and median survival 43 months vs 100 months, respectively; P < 0.001). Interestingly, when tumors were classified as either high or low for JAG1 mRNA or protein expression, there was only 65% agreement (kappa = 0.08) between the two methods of expression analysis. When JAG1 mRNA and protein data were combined, patients with tumors expressing low levels of both had a 10-year survival of 53% and median survival of 131 months. In comparison, patients with tumors expressing either high levels of JAG1 protein, mRNA or both had reduced 10-year survival and median survival (31%, 19%, 11% and 77, 43, 23 months respectively; P < 0.0001). There was marginal evidence of an interaction effect (P = 0.055), which indicated that the prognostic value of JAG1 protein was limited to the JAG1 mRNA-low subgroup. These data show that the Allred score can be used to rapidly quantify JAG1 mRNA and protein levels in breast cancer to identify patients who have a significant survival disadvantage and who may benefit from therapies (such as gamma-secretase inhibitors) that target signaling through the Notch pathway.