Cogswell P C, Guttridge D C, Funkhouser W K, Baldwin A S
Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, NC 27599-7295, USA.
Oncogene. 2000 Feb 24;19(9):1123-31. doi: 10.1038/sj.onc.1203412.
Members of the NF-kappa B/Rel transcription factor family have been shown recently to be required for cellular transformation by oncogenic Ras and by other oncoproteins and to suppress transformation-associated apoptosis. Furthermore, NF-kappa B has been shown to be activated by several oncoproteins including HER2/Neu, a receptor tyrosine kinase often expressed in human breast cancer. Human breast cancer cell lines, human breast tumors and normal adjacent tissue were analysed by gel mobility shift assay, immunoblotting of nuclear extracts and immunohistochemistry for activation of NF-kappa B. Furthermore, RNA levels for NF-kappa B-activated genes were analysed in order to determine if NF-kappa B is functionally active in human breast cancer. Our data indicate that the p65/RelA subunit of NF-kappa B is activated (i.e., nuclear) in breast cancer cell lines. However, breast tumors exhibit an absence or low level of nuclear p65/RelA but show activated c-Rel, p50 and p52 as compared to nontumorigenic adjacent tissue. Additionally, the I kappa B homolog Bcl-3, which functions to stimulate transcription with p50 or p52, was also activated in breast tumors. There was no apparent correlation between estrogen receptor status and levels of nuclear NF-kappa B complexes. Transcripts of NF-kappa B-regulated genes were found elevated in breast tumors, as compared to adjacent normal tissue, indicating functional NF-kappa B activity. These data suggest a potential role for a subset of NF-kappa B and I kappa B family proteins, particularly NF-kappa B/p52 and Bcl-3, in human breast cancer. Additionally, the activation of functional NF-kappa B in these tumors likely involves a signal transduction pathway distinct from that utilized by cytokines.
近来研究表明，核因子-κB/Rel转录因子家族成员是致癌性Ras及其他癌蛋白诱导细胞转化所必需的，且能抑制与转化相关的细胞凋亡。此外，核因子-κB已被证实可被多种癌蛋白激活，包括HER2/Neu，一种常在人类乳腺癌中表达的受体酪氨酸激酶。通过凝胶迁移率变动分析、核提取物免疫印迹以及免疫组化检测核因子-κB的激活情况，对人乳腺癌细胞系、人乳腺肿瘤及相邻正常组织进行了分析。此外，还分析了核因子-κB激活基因的RNA水平，以确定核因子-κB在人类乳腺癌中是否具有功能活性。我们的数据表明，核因子-κB的p65/RelA亚基在乳腺癌细胞系中被激活（即进入细胞核）。然而，乳腺肿瘤细胞核中的p65/RelA缺失或水平较低，但与非致瘤性相邻组织相比，c-Rel、p50和p52被激活。此外，与p50或p52共同发挥转录刺激作用的IκB同源物Bcl-3在乳腺肿瘤中也被激活。雌激素受体状态与细胞核内核因子-κB复合物水平之间无明显相关性。与相邻正常组织相比，核因子-κB调控基因的转录本在乳腺肿瘤中升高，表明核因子-κB具有功能活性。这些数据提示核因子-κB和IκB家族蛋白的一个子集，特别是核因子-κB/p52和Bcl-3，在人类乳腺癌中可能发挥潜在作用。此外，这些肿瘤中功能性核因子-κB的激活可能涉及一条不同于细胞因子所利用的信号转导途径。
