Epidermal growth factor-induced nuclear factor κB activation: A major pathway of cell-cycle progression in estrogen-receptor negative breast cancer cells

The epidermal growth factor (EGF) family of receptors (EGFR) is overproduced in estrogen receptor (ER) negative (−) breast cancer cells. An inverse correlation of the level of EGFR and ER is observed between ER− and ER positive (+) breast cancer cells. A comparative study with EGFR-overproducing ER− and low-level producing ER+ breast cancer cells suggests that EGF is a major growth-stimulating factor for ER− cells. An outline of the pathway for the EGF-induced enhanced proliferation of ER− human breast cancer cells is proposed. The transmission of mitogenic signal induced by EGF–EGFR interaction is mediated via activation of nuclear factor κB (NF-κB). The basal level of active NF-κB in ER− cells is elevated by EGF and inhibited by anti-EGFR antibody (EGFR-Ab), thus qualifying EGF as a NF-κB activation factor. NF-κB transactivates the cell-cycle regulatory protein, cyclin D1, which causes increased phosphorylation of retinoblastoma protein, more strongly in ER− cells. An inhibitor of phosphatidylinositol 3 kinase, Ly294–002, blocked this event, suggesting a role of the former in the activation of NF-κB by EGF. Go6976, a well-characterized NF-κB inhibitor, blocked EGF-induced NF-κB activation and up-regulation of cell-cycle regulatory proteins. This low molecular weight compound also caused apoptotic death, predominantly more in ER− cells. Thus Go6976 and similar NF-κB inhibitors are potentially novel low molecular weight therapeutic agents for treatment of ER− breast cancer patients.

表皮生长因子（epidermal growth factor, EGF）家族受体（EGFR）在雌激素受体（ER）阴性（−）乳腺癌细胞中过度表达。研究观察到，ER−与ER阳性（+）乳腺癌细胞中EGFR水平与ER呈负相关。针对EGFR高表达的ER−乳腺癌细胞与低表达的ER+乳腺癌细胞开展的对比研究表明，EGF是ER−细胞的主要生长刺激因子。本文提出了EGF诱导ER−人乳腺癌细胞增殖增强的信号通路概要：EGF与EGFR结合后诱导的有丝分裂原信号传递，通过核因子κB（nuclear factor κB, NF-κB）的激活介导。ER−细胞中活化NF-κB的基础水平可被EGF升高，同时可被抗EGFR抗体（EGFR-Ab）抑制，由此证实EGF可作为NF-κB激活因子。NF-κB可反式激活细胞周期调控蛋白细胞周期蛋白D1，该蛋白会促使视网膜母细胞瘤蛋白磷酸化水平升高，在ER−细胞中这一效应更为显著。磷脂酰肌醇3激酶抑制剂Ly294–002可阻断这一过程，提示该激酶在EGF介导的NF-κB激活中发挥作用。Go6976是一种特性明确的NF-κB抑制剂，可阻断EGF诱导的NF-κB激活以及细胞周期调控蛋白的上调。该小分子化合物还可诱导细胞凋亡性死亡，在ER−细胞中这一作用更为显著。因此，Go6976及同类NF-κB抑制剂有望成为治疗ER−乳腺癌患者的新型小分子治疗药物。