The mitogen-activated protein kinases (MAPK) p38 and JNK are markers of tumor progression in breast carcinoma
The mitogen-activated protein kinases (MAPK) p38 and JNK are markers of tumor progression in breast carcinoma
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DOI：
10.1016/j.ygyno.2006.01.034
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发表时间：
2006-09-01
影响因子：
4.7
通讯作者：
Reich, Reuven
中科院分区：
文献类型：
--
作者：
Davidson, Ben;Konstantinovsky, Sophya;Reich, Reuven
目标。探讨乳腺癌积液中丝裂原活化蛋白激酶（MAPK）的活化情况，并分析其与解剖部位及临床指标的关系。应用免疫组化（IHC）技术研究了42例积液和51例实体瘤（23例原发瘤，28例转移瘤）中活化MAPK （p-ERK、p-JNK和p-p38）的表达。评估激素受体和HER2状态、增殖（Ki-67）和凋亡（p85-PARP片段）。应用免疫印迹法分析19例积液中MAPK水平、活性和活化比（磷酸化/泛MAPK比）（113）。与原发肿瘤（P - jnk P < 0.001, P -p38 P = 0.011）和淋巴结转移（P - jnk P = 0.003, P -p38 P = 0.025）相比，积液中P -p38和P - jnk的核表达显著升高，但不伴有细胞凋亡。113例中，pan-ERK和p-ERK分别出现在18/19和17/19中，pan-JNK和p-JNK分别出现在18/19和17/19中，pan-p38和p-p38分别出现在19/19和17/19中。在所有病例的单因素生存分析中，病程晚期（P = 0.041）、既往化疗（P = 0.004）、放疗（P = 0.001）和Ki-67评分较高（P = 0.01）与总生存（OS）差相关。在Cox多因素分析中，分期（P = 0.018）、化疗（P = 0.024）、放疗（P = 0.017）和ER状态（P = 0.002）是OS的独立预后因素。113例数据的定量分析显示，p38激活率越高，OS越短（P = 0.01）。本研究提供了MAPK在乳腺癌组织中激活的第一个证据。积液中JNK和p38激活的升高可能是一种应激相关的机制，为乳腺癌细胞提供了生存优势，而不是导致细胞凋亡。p38和Ki-67可能是乳腺癌积液患者预后的新指标。(c) 2006爱思唯尔公司版权所有。
Objective. To investigate the activation of mitogen-activated protein kinases (MAPK) in breast carcinoma effusions and to analyze its relationship to anatomic site and clinical parameters.Methods. Activated MAPK (p-ERK, p-JNK, and p-p38) expression was studied in 42 effusions and 51 corresponding solid tumors (23 primary, 28 metastases) using immunohistochemistry (IHC). Hormone receptor and HER2 status, proliferation (Ki-67), and apoptosis (p85-PARP fragment) were assessed. MAPK levels, activity, and activation ratio (phospho/pan-MAPK ratio) were analyzed in 19 effusions using immunoblotting (113).Results. Nuclear expression of p-p38 and p-JNK was significantly higher in effusions compared with both primary tumors (P < 0.001 for p-JNK, P = 0.011 for p-p38) and lymph node metastases (P = 0.003 for p-JNK, P = 0.025 for p-p38) but was not accompanied by apoptosis. 113 showed pan-ERK and p-ERK in 18/19 effusions, pan-JNK and p-JNK in 18/19 and 17/19 effusions, respectively, and pan-p38 and p-p38 in 19/19 and 17/19 specimens, respectively. In univariate survival analysis of all cases, advanced disease stage (P = 0.041), previous chemotherapy (P = 0.004), and radiation (P = 0.001) and higher Ki-67 scores (P = 0.01) correlated with worse overall survival (OS). In Cox multivariate analysis, stage (P = 0.018), chemotherapy (P = 0.024), radiation (P = 0.017), and ER status (P = 0.002) were independent prognosticators of OS. Quantitative analysis of 113 data showed that higher p38 activation ratio correlates with shorter OS (P = 0.01).Conclusions. This study presents first evidence of in vivo activation of MAPK in breast carcinoma efftisions. The elevated JNK and p38 activation in effusions may be a stress-related mechanism providing breast carcinoma cells with survival advantages rather than a drive towards apoptosis. p38 and Ki-67 may be new prognostic markers for patients with breast cancer effusions. (c) 2006 Elsevier Inc. All rights reserved.