Sovak M A, Arsura M, Zanieski G, Kavanagh K T, Sonenshein G E
Department of Pathology and Laboratory Medicine, Boston University Medical School, Massachusetts 02118, USA.
Cell Growth Differ. 1999 Aug;10(8):537-44.
Nuclear factor (NF)-kappaB/Rel transcription factors normally exist in non-B cells, such as epithelial cells, in inactive forms sequestered in the cytoplasm with specific inhibitory proteins, termed IkappaBs. Recently, however, we discovered that breast cancer is typified by aberrant constitutive expression of NF-kappaB/Rel factors. Because these factors control genes that regulate cell proliferation, here we analyzed the potential role of NF-kappaB/Rel in the ability of transforming growth factor (TGF)-beta1 to inhibit the growth of breast cancer cells. The decreased growth of Hs578T and MCF7 breast cancer cell lines on TGF-beta1 treatment correlated with a drop in NF-kappaB/Rel binding. This decrease was due to the stabilization of the inhibitory protein IKB-alpha. Ectopic expression of c-Rel in Hs578T cells led to the maintenance of NF-kappaB/Rel binding and resistance to TGF-beta1-mediated inhibition of proliferation. Similarly, expression of the p65 subunit ablated the inhibition of Hs578T cell growth mediated by TGF-beta1. Thus, the inhibition of the aberrantly activated, constitutive NF-kappaB/Rel plays an important role in the arrest of the proliferation of breast cancer cells, which suggests that NF-kappaB/Rel may be a useful target in the treatment of breast cancer.
核因子（NF）-κB/Rel转录因子通常以非活性形式存在于非B细胞（如上皮细胞）中，与特定的抑制蛋白IκB结合并被隔离在细胞质中。然而，最近我们发现乳腺癌的典型特征是NF-κB/Rel因子的异常组成性表达。由于这些因子控制着调节细胞增殖的基因，因此我们在此分析了NF-κB/Rel在转化生长因子（TGF）-β1抑制乳腺癌细胞生长能力中的潜在作用。TGF-β1处理后，Hs578T和MCF-7乳腺癌细胞系的生长减缓与NF-κB/Rel结合的下降相关。这种下降是由于抑制蛋白IκB-α的稳定化。在Hs578T细胞中异位表达c-Rel导致NF-κB/Rel结合的维持以及对TGF-β1介导的增殖抑制的抗性。同样，p65亚基的表达消除了TGF-β1对Hs578T细胞生长的抑制作用。因此，抑制异常激活的组成性NF-κB/Rel在乳腺癌细胞增殖停滞中起重要作用，这表明NF-κB/Rel可能是乳腺癌治疗中的一个有用靶点。
