Targeting Fibroblast Growth Factor Receptors Blocks PI3K/AKT Signaling, Induces Apoptosis, and Impairs Mammary Tumor Outgrowth and Metastasis
Targeting Fibroblast Growth Factor Receptors Blocks PI3K/AKT Signaling, Induces Apoptosis, and Impairs Mammary Tumor Outgrowth and Metastasis
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DOI：
10.1158/0008-5472.can-09-4479
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发表时间：
2010-05-15
期刊：
影响因子：
11.2
通讯作者：
Hynes, Nancy E.
中科院分区：
文献类型：
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作者：
Dey, Julien H.;Bianchi, Fabrizio;Hynes, Nancy E.
成纤维细胞生长因子受体 (FGFR) 家族的成员在正常生理和癌症中发挥着重要作用，它们控制着不同的过程。 FGFR 与乳腺癌的发生有关。因此，研究 FGFR 在乳腺癌中的作用及其靶向潜力的模型非常重要。我们对乳腺癌模型细胞系 67NR 和 4T1 中的 FGFR 进行了体外和体内分析。我们发现两种肿瘤细胞系共表达 FGFR 和配体，并显示自分泌 FGFR 信号传导活性。成纤维细胞生长因子受体底物 2 (FRS2) 是 FGFR 的下游介质，被组成型酪氨酸磷酸化，并且多个信号传导途径处于活跃状态。用 TKI258（一种 FGFR 酪氨酸激酶抑制剂 (TKI)）处理 67NR 和 4T1 培养物，导致 FRS2 磷酸化迅速降低；降低细胞外信号调节激酶 1/2 (ERK1/2)、AKT 和磷脂酶 C 的活性；并阻断两种肿瘤系的增殖。此外，TKI258 通过阻断磷酸肌醇 3-激酶/AKT 途径诱导 4T1 凋亡细胞死亡。在体内，一剂 TKI258 迅速降低乳腺肿瘤中的 FRS2 磷酸化以及 ERK1/2 和 AKT 活性。长期 TKI258 治疗 4T1 肿瘤和 67NR 肿瘤小鼠对原发肿瘤生长和 4T1 肿瘤诱导的肺转移有显着影响。进行微阵列分析以确定在 TKI258 抗肿瘤活性中起作用的靶点和人类乳腺肿瘤中的潜在预后标志物。令人感兴趣的是下调的基质金属蛋白酶 (MMP)，特别是 MMP9，它对于 4T1 肿瘤的转移扩散至关重要。癌症研究； 70（10）； 4151-62。 (C) 2010 AACR。
Members of the fibroblast growth factor receptor ( FGFR) family have essential roles in normal physiology and in cancer where they control diverse processes. FGFRs have been associated with breast cancer development. Thus, models to study the role of FGFR in breast cancer and their targeting potential are important. We present an in vitro and in vivo analysis of FGFRs in the breast cancer model cell lines 67NR and 4T1. We show that both tumor cell lines coexpress FGFRs and ligands and display autocrine FGFR signaling activity. Fibroblast growth factor receptor substrate 2 (FRS2), a downstream mediator of FGFR, is constitutively tyrosine phosphorylated and multiple signaling pathways are active. Treatment of 67NR and 4T1 cultures with TKI258, an FGFR tyrosine kinase inhibitor (TKI), caused a rapid decrease in FRS2 phosphorylation; decreased the activity of extracellular signal-regulated kinase 1/2 (ERK1/2), AKT, and phospholipase C.; and blocked proliferation of both tumor lines. Furthermore, TKI258 induced 4T1 apoptotic cell death via blockade of the phosphoinositide 3-kinase/AKT pathway. In vivo, one dose of TKI258 rapidly lowered FRS2 phosphorylation and ERK1/2 and AKT activity in mammary tumors. Long-term TKI258 treatment of 4T1 tumor- and 67NR tumor-bearing mice had a significant effect on primary tumor outgrowth and 4T1 tumor-induced lung metastases. A microarray analysis was carried out to identify targets with roles in TKI258 antitumor activity and potential prognostic markers in human breast tumors. Of interest are the downregulated matrix metalloproteases (MMP), in particular MMP9, which is essential for metastatic spread of 4T1 tumors. Cancer Res; 70( 10); 4151-62. (C) 2010 AACR.