三阴性乳腺癌中 Notch1、pAKT 和核 NF-κB 表达的相关性。
Correlation of Notch1, pAKT and nuclear NF-κB expression in triple negative breast cancer.
机构信息
Cancer Institute, University of Mississippi Medical Center Jackson, MS 39216 ; Department of Pathology, University of Mississippi Medical Center Jackson, MS 39216.
出版信息
Am J Cancer Res. 2013 Apr 3;3(2):230-9. Print 2013.
Gene expression profiling reveals elevated Notch1 mRNA expression in triple negative breast cancers (TNBC), both basaloid and claudin-low subtypes. Notch ligands, Jagged1 and Jagged2, have been correlated with poor prognosis in TNBC. AKT, an oncogenic protein kinase family that is activated downstream of Notch in breast cancer cell lines, is frequently activated in breast cancer. Recent publications suggest that inhibition of cell growth, migration, invasion, and induction of apoptosis caused by Notch1 or Jagged1 inhibition may be attributed in part to inactivation of the AKT signaling pathway. There is significant evidence that Notch1 activates NF-κB in several models, and that AKT can mediate NF-κB activation. In this study, we evaluated Notch1 protein expression by immunohistochemistry (IHC) and correlated this with expression of pAKT and nuclear NF-κB p65 (RelA) in TNBC. A tissue microarray (TMA) containing 32 formalin-fixed, paraffin-embedded (FFPE) TNBC tumor specimens was constructed from the archival tissue database of the Department of Pathology at UMMC and IHC for Notch1 protein, pAKT 1/2/3 (Ser473), and NF-κB, p65 subunit was performed on the TMA with appropriate positive and negative controls. Of the 32 TNBC in our cohort, 100% expressed Notch1 protein by IHC: 24 (75%) showed cytoplasmic expression, 25 (78%) showed membranous expression, and 17 (53%) showed both cytoplasmic and membranous expression. Overall, 29 (91%) expressed pAKT by IHC: 28 (97%) showed cytoplasmic expression, 14 (48%) showed nuclear expression and 13 (45%) showed both cytoplasmic and nuclear expression. Nuclear staining for NF-κB p65 was detected in all 32 TNBC specimens with variable intensities. On bivariate analysis, cytoplasmic Notch1 was significantly correlated with cytoplasmic pAKT (r = 0.373, P = 0.035) and nuclear NF-κB (r = 0.483, P = 0.005); both cytoplasmic and nuclear pAKT significantly correlated with nuclear NF-κB (r = 0.391, P = 0.027; r = 0.525, P = 0.002, respectively). These results suggest that 1) the cross-talk between Notch1, AKT and NF-κB identified in preclinical models may operate in a significant fraction of human TNBC, and 2) combination therapy with agents targeting these pathways warrants further investigation.
基因表达谱分析显示，三阴性乳腺癌（TNBC）中 Notch1 mRNA 表达水平升高，包括基底样和 Claudin-低表达亚型。Notch 配体 Jagged1 和 Jagged2 与 TNBC 的不良预后相关。AKT 是一种致癌蛋白激酶家族，在乳腺癌细胞系中 Notch 的下游被激活，在乳腺癌中经常被激活。最近的出版物表明，Notch1 或 Jagged1 抑制引起的细胞生长、迁移、侵袭和诱导凋亡部分归因于 AKT 信号通路的失活。有大量证据表明，Notch1 在几种模型中激活 NF-κB，而 AKT 可以介导 NF-κB 的激活。在这项研究中，我们通过免疫组织化学（IHC）评估了 TNBC 中的 Notch1 蛋白表达，并将其与 pAKT 和核 NF-κB p65（RelA）的表达相关联。从 UMMC 病理学系的档案组织数据库中构建了包含 32 例福尔马林固定、石蜡包埋（FFPE）TNBC 肿瘤标本的组织微阵列（TMA），并对 TMA 进行 Notch1 蛋白、pAKT 1/2/3（Ser473）和 NF-κB、p65 亚基的 IHC 检测，同时使用适当的阳性和阴性对照。在我们的队列中，32 例 TNBC 中有 100%通过 IHC 表达 Notch1 蛋白：24 例（75%）表现为细胞质表达，25 例（78%）表现为膜表达，17 例（53%）表现为细胞质和膜表达。总体而言，29 例（91%）通过 IHC 表达 pAKT：28 例（97%）表现为细胞质表达，14 例（48%）表现为核表达，13 例（45%）表现为细胞质和核表达。NF-κB p65 的核染色在所有 32 例 TNBC 标本中均有不同强度的检测到。在双变量分析中，细胞质 Notch1 与细胞质 pAKT（r = 0.373，P = 0.035）和核 NF-κB（r = 0.483，P = 0.005）显著相关；细胞质和核 pAKT 与核 NF-κB 均显著相关（r = 0.391，P = 0.027；r = 0.525，P = 0.002）。这些结果表明：1）在临床前模型中鉴定的 Notch1、AKT 和 NF-κB 之间的串扰可能在人类 TNBC 的很大一部分中起作用，2）针对这些途径的联合治疗值得进一步研究。
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