Horii Rie, Matsuura Masaaki, Dan Shingo, Ushijima Masaru, Uehiro Natsue, Ogiya Akiko, Honma Naoko, Ito Yoshinori, Iwase Takuji, Yamori Takao, Akiyama Futoshi
Department of Pathology, Cancer Institute, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan,
Int J Clin Oncol. 2015 Jun;20(3):490-8. doi: 10.1007/s10147-014-0753-8. Epub 2014 Oct 15.
The aim of this study was to extensively analyze the signaling pathway molecules in breast cancer and to explore candidate biomarkers for clinicopathological relevance.
We assessed the expression of key factors in cell signaling, namely p-AKT, cyclin D1, P27, p-p70S6 K, p-4EBP1, and p-MAPK/ERK, within 338 invasive breast cancer patients. These factors were immunohistochemically examined in tumor tissues and assessed by staining score. Staining scores were analyzed by a clustering method to devise a new classification based on pathway activity. We investigated the relationships among staining scores, the clustering classification, and patient characteristics.
The proportion of patients displaying high expression levels were as follows: p-AKT, 75%; cyclin D1, 12%; P27, 53%; p-p70S6 K, 37%; p-4EBP1, 19%; and p-MAPK/ERK, 3%. Patients were classified into two groups on the basis of staining scores. Group 1 (39%) included more positive cases for p-4EBP1, p-MAPK/ERK, and p-p70S6 K and fewer positive cases for P27 and cyclin D1 than Group 2 (61%). The clustering classification was significantly related to subgrouping by hormone receptor and HER2 (P < 0.001), nuclear grade (P < 0.001) and histological subtype (P = 0.034). A strong positive correlation was identified between p-AKT and P27, cyclin D1 and P27, p-p70S6 K and p-4EBP1, p-p70S6 K and p-MAPK/ERK, and between p-4EBP1 and p-MAPK/ERK. Levels of p-p70S6 K were significantly related to recurrence in both univariate (RR = 0.75, P < 0.001) and multivariate (RR = 0.71, P = 0.049) analyses.
The present study helps us to understand the characteristics of signaling pathway status in breast cancers. Moreover, p-p70S6 K expression may be of use in predicting clinical outcome.
本研究旨在广泛分析乳腺癌中的信号通路分子，并探索与临床病理相关性的候选生物标志物。
我们评估了338例浸润性乳腺癌患者细胞信号传导关键因子的表达，即p-AKT、细胞周期蛋白D1、P27、p-p70S6 K、p-4EBP1和p-MAPK/ERK。这些因子在肿瘤组织中进行免疫组织化学检测，并通过染色评分进行评估。通过聚类方法分析染色评分，以基于通路活性设计新的分类。我们研究了染色评分、聚类分类与患者特征之间的关系。
显示高表达水平的患者比例如下：p-AKT为75%；细胞周期蛋白D1为12%；P27为53%；p-p70S6 K为37%；p-4EBP1为19%；p-MAPK/ERK为3%。根据染色评分将患者分为两组。与第2组（61%）相比，第1组（39%）中p-4EBP1、p-MAPK/ERK和p-p70S6 K的阳性病例更多，而P27和细胞周期蛋白D1的阳性病例更少。聚类分类与激素受体和HER2亚组（P < 0.001）、核分级（P < 0.001）及组织学亚型（P = 0.034）显著相关。在p-AKT与P27、细胞周期蛋白D1与P27、p-p70S6 K与p-4EBP1、p-p70S6 K与p-MAPK/ERK以及p-4EBP1与p-MAPK/ERK之间发现了强正相关。在单因素（RR = 0.75，P < 0.001）和多因素（RR = 0.71，P = 0.049）分析中，p-p70S6 K水平与复发均显著相关。
本研究有助于我们了解乳腺癌中信号通路状态的特征。此外，p-p70S6 K表达可能有助于预测临床结局。
