Vleugel Marije M, Greijer Astrid E, Bos Reinhard, van der Wall Elsken, van Diest Paul J
Department of Pathology, University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands.
Hum Pathol. 2006 Jun;37(6):668-74. doi: 10.1016/j.humpath.2006.01.022.
c-Jun is a component of the transcription factor activator protein 1 (AP-1), which binds and activates transcription at TRE/AP-1 elements. Extra- or intracellular signals, including growth factors, transforming oncoproteins, and UV irradiation, stimulate phosphorylation of c-Jun at serine 63/73 and activate c-Jun-dependent transcription. Therefore, activated c-Jun potentially plays an important role in carcinogenesis and cancer progression. To evaluate expression patterns of activated c-Jun in breast cancer in relation to angiogenesis and proliferation, we performed immunohistochemistry on 103 cases of invasive breast cancer with an antibody recognizing phosphorylated c-Jun at serine 73. Activated c-Jun showed a predominantly nuclear expression at the invasive front in 38% of invasive breast cancer cases. Furthermore, expression of activated c-Jun was seen in mitotic cells of the invasive front in 50% of cases. Occasionally, fibroblasts, endothelial cells, and benign breast cells showed nuclear expression. Activated nuclear c-Jun expression showed positive correlations with expression of hyperphosphorylated pRb, vascular endothelial growth factor, and with microvessel density. Mitotic c-Jun expression was associated with pRb and microvessel density. Stromal c-Jun expression showed positive relations with microvessel density. In survival analysis, no significant relation was found with activated c-Jun expression and survival, although a trend with poor survival was found for mitotic cells overexpressing activated c-Jun (P = .09). Our results show that activated c-Jun is predominantly expressed at the invasive front in breast cancer and is associated with proliferation and angiogenesis. Earlier studies have established a functional, in vitro link between activated c-Jun and tumor angiogenesis. Our present results in breast cancer patients confirm this relation in vivo for the first time. Therefore, c-Jun/AP-1 targeting may provide new ways to block tumor angiogenesis.
c-Jun是转录因子激活蛋白1（AP-1）的一个组成部分，AP-1可在TRE/AP-1元件处结合并激活转录。细胞外或细胞内信号，包括生长因子、转化癌蛋白和紫外线照射，可刺激c-Jun在丝氨酸63/73处磷酸化并激活c-Jun依赖性转录。因此，活化的c-Jun可能在致癌作用和癌症进展中发挥重要作用。为了评估活化的c-Jun在乳腺癌中与血管生成和增殖相关的表达模式，我们用一种识别丝氨酸73处磷酸化c-Jun的抗体对103例浸润性乳腺癌进行了免疫组织化学检测。在38%的浸润性乳腺癌病例中，活化的c-Jun在浸润前沿主要呈核表达。此外，在50%的病例中，浸润前沿的有丝分裂细胞中可见活化的c-Jun表达。偶尔，成纤维细胞、内皮细胞和良性乳腺细胞也呈核表达。活化的核c-Jun表达与高磷酸化pRb、血管内皮生长因子的表达以及微血管密度呈正相关。有丝分裂期c-Jun表达与pRb和微血管密度相关。基质c-Jun表达与微血管密度呈正相关。在生存分析中，未发现活化的c-Jun表达与生存之间存在显著关系，尽管在过表达活化c-Jun的有丝分裂细胞中发现了生存不良的趋势（P = 0.09）。我们的结果表明，活化的c-Jun在乳腺癌的浸润前沿主要表达，并与增殖和血管生成相关。早期研究已在体外建立了活化的c-Jun与肿瘤血管生成之间的功能联系。我们目前在乳腺癌患者中的结果首次在体内证实了这种关系。因此，靶向c-Jun/AP-1可能为阻断肿瘤血管生成提供新方法。
