AKT、NF-кB及STAT3在有淋巴结转移及雌激素受体阳性的乳腺癌组织中的活化及其意义

Activation and Prognostic Significance of AKT, NF-кB and STAT3 in Breast Cancer with Lymph Node Metastasis and Estrogen Receptor Expression

背景与目的:蛋白酪氨酸磷酸酶基因(phosphatase and tensin homolog deleted on chromosome ten,PTEN)与表皮生长因子受体(epidermal growth factor receptor,EGFR)信号途径的下游因子丝-苏氨酸激酶AKT、核因子-кB(nuclear factor-kappa B,NF-кB)以及信号转导子和转录激活子-3(signal transducer and activator of transcription-3,STAT3)与恶性肿瘤的发生、增殖与凋亡过程关系密切。本研究探讨AKT、NF-кB及STAT3在有淋巴结转移及雌激素受体阳性的乳腺癌组织中的活化情况及其与患者预后的关系。方法:免疫组化法检测130例雌激素受体阳性和有腋窝淋巴结转移的乳腺癌患者肿瘤组织中磷酸化AKT、NF-кB及STAT3的表达,以反映三者在肿瘤组织中的活化状态。同时检测这些组织中EGFR、PTEN、Ki67及HER-2的表达。结果:高活化状态的AKT(p-AKT)和NF-кB(p-NF-кB)与HER-2过度表达显著相关(分别P=0.023和P=0.017),并随着肿瘤组织学级别的升高表达显著增强(分别P=0.035和P=0.004)。而p-AKT、p-NF-кB和p-STAT3与肿瘤大小、EGFR的过度表达以及Ki67所反映的增殖状况无关,但p-AKT和p-NF-кB的表达呈显著正相关(r=0.43,P<0.001)而与PENT的表达呈显著负相关(r=-0.20,P=0.002)。单因素生存分析显示p-AKT和p-NF-кB在肿瘤组织中过度表达的患者生存期显著缩短(分别P=0.005和P=0.003),而且p-NF-кB表达增加也预示患者较高的复发或转移的可能性(P=0.006)。Cox分析发现,p-AKT和p-NF-кB的过度表达与患者总生存期(OS)(分别P=0.017和P=0.008)及患者无病生存期(DFS)(分别P=0.005和P=0.012)缩短显著相关,但p-STAT3的表达与OS和DFS无相关性(分别P=0.332和P=0.237)。结论:AKT和NF-кB在乳腺癌组织中的活化与肿瘤的发展显著相关,在有腋窝淋巴结转移及ER阳性的癌组织中p-AKT和p-NF-кB过度表达是乳腺癌患者预后不良的判断因子之一。

BACKGROUND ＆ OBJECTIVE： Being downstream targets of the phosphatase and tensin homolog deleted on chromosome ten （PTEN） and epidermal growth factor receptor （EGFR） pathways, serine/threonine kinase AKT, nuclear factor-кB （NF-кB） and signal transducer and activator of transcription-3 （STAT3）, play important roles in cell proliferation, apoptosis and oncogenesis. This study was to investigate the activation and prognostic values of AKT, NF-кB and STAT3 in breast cancer with lymph node metastasis and estrogen receptor （ER） expression. METHODS： The expression of phosphatized AKT （p-AKT）, NF-кB （p-NF-кB） and STAT3 （p-STAT3）, and the expression of EGFR, PTEN, HER-2, and Ki67 in tissue samples from 130 breast cancer patients with lymph node metastasis and ER expression were detected by immunohistochemistry. RESULTS： The activity of AKT （p-AKT） and NF-кB （p-NF-кB） were correlated to HER-2 overexpression （P=0.023 and P=0.017） and histological grade of breast cancer （P=0.035 and P=0.004）. The expression of p-AKT, p-NF-кB and p-STAT3 had no correlation to tumor size, EGFR overexpression, and proliferation index assessed by Ki67. The expression of p-AKT was positively correlated to that of p-NF-кB （r=0.43, P〈0.001） and negatively correlated to that of p-PTEN （r=-0.20, P=0.002）. The overexpression of p-AKT and p-NF-кB were significantly related to shorter survival （P=0.002 and P=0.003）. The up-regulation of p-NF-кB expression was also related to enhanced risk of recurrence and metastasis （P=0.006）. Cox multivariate analysis showed that the expression of p-AKT and p-NF-кB were correlated to shorter overall survival （OS） （P=0.017 and P=0.008） and disease-free survival （DFS） （P=0.005 and P=0.012）, while the expression of p-STAT3 had no correlation to OS （P=0.332） and DFS （P=0.237）. CONCLUSIONS： The activation of AKT and NF-кB, but not STAT3, significantly contributes to the progression of breast cancer. Activated AKT and NF-кB may indicate poor prognosis of breast cancer with lymph node metastasis and ER expression.