Rojo Federico, Najera Laura, Lirola José, Jiménez José, Guzmán Marta, Sabadell M Dolors, Baselga Jose, Ramon y Cajal Santiago
Department of Pathology, Vall d'Hebron University Hospital, Barcelona, Spain.
Clin Cancer Res. 2007 Jan 1;13(1):81-9. doi: 10.1158/1078-0432.CCR-06-1560.
Cell signaling pathways include a complex myriad of interconnected factors from the membrane to the nucleus, such as erbB family receptors and the phosphoinositide-3-kinase/Akt/mTOR and Ras-Raf-ERK cascades, which drive proliferative signals, promote survival, and regulate protein synthesis.
To find pivotal factors in these pathways, which provide prognostic information in malignancies, we studied 103 human breast tumors with an immunohistochemical profile, including total and phosphorylated (p) proteins: human epidermal growth factor receptor 2 (HER2), epidermal growth factor receptor, extracellular signal-regulated kinase 1/2, Akt, 4E-binding protein 1 (4EBP1), eukaryotic initiation factor 4E, phosphorylated ribosomal protein S6 kinase 1, phosphorylated ribosomal protein S6, and Ki67. Western blot and reverse lysate protein arrays were also done in a subset of tumors.
Significantly, activation of the phosphoinositide-3-kinase/Akt/mTOR cascade was detected in a high proportion of tumors (41.9%). Tumors with HER2 overexpression showed higher p-Akt as compared with negative tumors (P < 0.001). Levels of p-Akt correlated with the downstream molecules, p-4EBP1 (P = 0.001) and p-p70S6K (P = 0.05). Although 81.5% of tumors expressed p-4EBP1, in 16.3% of these tumors, concomitant activation of the upstream factors was not detected. Interestingly, p-4EBP1 was mainly expressed in poorly differentiated tumors (P < 0.001) and correlated with tumor size (P < 0.001), presence of lymph node metastasis (P = 0.002), and locoregional recurrences (P = 0.002). Coexpression of p-4EBP1 and p-eIF4G correlated with a high tumor proliferation rate (P = 0.012).
In this study, p-4EBP1 was the main factor in signaling pathways that associate with prognosis and grade of malignancy in breast tumors. Moreover, p-4EBP1 was detected in both HER2-positive and HER2-negative tumors. This factor seems to be a channeling point at which different upstream oncogenic alterations converge and transmit their proliferative signal, modulating protein translation.
细胞信号通路包含从细胞膜到细胞核的大量复杂且相互关联的因子，如erbB家族受体以及磷酸肌醇-3-激酶/蛋白激酶B/哺乳动物雷帕霉素靶蛋白（PI3K/Akt/mTOR）和Ras-Raf-ERK级联反应，这些因子驱动增殖信号、促进细胞存活并调节蛋白质合成。
为了找到这些通路中能为恶性肿瘤提供预后信息的关键因子，我们对103例人类乳腺肿瘤进行了免疫组化分析，检测了包括总蛋白和磷酸化（p）蛋白在内的多种蛋白：人表皮生长因子受体2（HER2）、表皮生长因子受体、细胞外信号调节激酶1/2、蛋白激酶B、4E结合蛋白1（4EBP1）、真核起始因子4E、磷酸化核糖体蛋白S6激酶1、磷酸化核糖体蛋白S6以及Ki67。还对一部分肿瘤进行了蛋白质免疫印迹和反向裂解物蛋白芯片检测。
值得注意的是，在高比例的肿瘤（41.9%）中检测到磷酸肌醇-3-激酶/蛋白激酶B/哺乳动物雷帕霉素靶蛋白级联反应的激活。HER2过表达的肿瘤与阴性肿瘤相比，p-Akt水平更高（P<0.001）。p-Akt水平与下游分子p-4EBP1（P = 0.001）和p-p70S6K（P = 0.05）相关。尽管81.5%的肿瘤表达p-4EBP1，但在其中16.3%的肿瘤中未检测到上游因子的伴随激活。有趣的是，p-4EBP1主要在低分化肿瘤中表达（P<0.001），并与肿瘤大小（P<0.001）、淋巴结转移情况（P = 0.002）以及局部复发（P = 0.002）相关。p-4EBP1和p-eIF4G的共表达与高肿瘤增殖率相关（P = 0.012）。
在本研究中，p-4EBP1是与乳腺肿瘤预后和恶性程度相关的信号通路中的主要因子。此外，在HER2阳性和HER2阴性肿瘤中均检测到p-4EBP1。该因子似乎是一个汇聚点，不同的上游致癌改变在此汇聚并传递其增殖信号，从而调节蛋白质翻译。
