Mammary tumorigenesis induced by fibroblast growth factor receptor 1 requires activation of the epidermal growth factor receptor
Mammary tumorigenesis induced by fibroblast growth factor receptor 1 requires activation of the epidermal growth factor receptor
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DOI：
10.1242/jcs.082651
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发表时间：
2011-09-15
影响因子：
4
通讯作者：
Schwertfeger, Kathryn L.
中科院分区：
文献类型：
--
作者：
Bade, Lindsey K.;Goldberg, Jodi E.;Schwertfeger, Kathryn L.
成纤维细胞生长因子受体1（FGFR 1）是一种已知参与乳腺肿瘤发生的癌蛋白。为了了解FGFR 1信号传导如何促进乳腺肿瘤发生，先前创建了诱导型FGFR 1（iFGFR 1）系统。先前的研究已经证明，在体内iFGFR 1活化后，表皮生长因子（EGF）配体双调蛋白（AREG）和表皮调节蛋白（EREG）上调。AREG和EREG都与EGF受体（EGFR）相互作用。在这里，我们研究了FGFR 1诱导的AREG和EREG表达的增加是否可能协同增加EGFR信号传导以促进乳腺肿瘤发生。用AREG或EREG处理小鼠乳腺上皮细胞赋予更大的迁移潜力，增加细胞增殖和增加细胞外调节激酶1/2（ERK 1/2）活化。这些作用可以用EGFR特异性抑制剂厄洛替尼阻断，表明它们是EGFR依赖性的。在小鼠乳腺肿瘤病毒（MMTV）启动子控制下的iFGFR 1转基因小鼠中，iFGFR 1激活也导致乳腺上皮细胞增殖增加，而厄洛替尼可抑制乳腺上皮细胞增殖。总之，这些数据表明AREG和EREG通过激活EGFR信号传导介导致瘤表型，并且FGFR 1的致癌潜力需要EGFR激活以促进乳腺肿瘤发生。
Fibroblast growth factor receptor 1 (FGFR1) is an oncoprotein with known involvement in mammary tumorigenesis. To understand how FGFR1 signaling promotes mammary tumorigenesis, an inducible FGFR1 (iFGFR1) system was created previously. Previous studies have demonstrated that upon iFGFR1 activation in vivo, the epidermal growth factor (EGF) ligands amphiregulin (AREG) and epiregulin (EREG) are upregulated. Both AREG and EREG interact with the EGF receptor (EGFR). Here, we investigated whether the FGFR1-induced increase in AREG and EREG expression might coordinately increase EGFR signaling to promote mammary tumorigenesis. Treatment of mouse mammary epithelial cells with either AREG or EREG conferred a greater migratory potential, increased cellular proliferation and increased extracellular regulated kinase 1/2 (ERK1/2) activation. These effects could be blocked with the EGFR-specific inhibitor erlotinib, suggesting that they are EGFR-dependent. In transgenic mice with iFGFR1 under the control of the mouse mammary tumor virus (MMTV) promoter, iFGFR1 activation also led to increased mammary epithelial cell proliferation that was inhibited with erlotinib. Taken together, these data suggest that AREG and EREG mediate tumorigenic phenotypes by activating EGFR signaling, and that the oncogenic potential of FGFR1 requires EGFR activation to promote mammary tumorigenesis.