FGFR1是一种受体酪氨酸激酶，在某些乳腺癌（BCs）中出现失调，预后不良。尽管FGFR1激活的磷酸化级联已被绘制，但FGFR1在BC中调节的关键基因仍不清楚。FOXQ1是一个致癌转录因子。虽然我们发现FGFR1的激活能够强烈上调 FOXQ1 mRNA，但是FGFR1如何调节 FOXQ1基因表达及其是否对FGFR1刺激的细胞增殖至关重要仍不得而知。在此，我们证实，在BC细胞中激活FGFR1能够强烈上调FOXQ1 mRNA和蛋白质表达。敲除FOXQ1阻断了FGFR1信号刺激的乳腺癌细胞增殖、集落形成和异种移植肿瘤生长。抑制MEK或ERK1/2活性，或敲除ERK2但不是ERK1抑制了FGFR1信号促进的 FOXQ1基因表达。在ERK1敲除细胞中抑制ERK2阻断了由FGFR1促进的细胞生长，而在ERK2敲除细胞中过度表达FOXQ1则可以挽救FGFR1信号促进的细胞生长。就机制而言，由FGFR1-MEK-ERK2途径上调的早期应答转录因子c-FOS结合到FOXQ1启动子上以介导FGFR1信号促进的FOXQ1表达。这些结果表明FGFR1-ERK2-c-FOS-FOXQ1调控轴在FGFR1信号促进的BC生长中起着重要作用。靶向ERK2和FOXQ1可以阻断由失调的FGFR1信号引起的BC生长。©作者。

FGFR1 is a receptor tyrosine kinase deregulated in certain breast cancers (BCs) with a poor prognosis. Although FGFR1-activated phosphorylation cascades have been mapped, the key genes regulated by FGFR1 in BC are largely unclear. FOXQ1 is an oncogenic transcription factor. Although we found that activation of FGFR1 robustly upregulated FOXQ1 mRNA, how FGFR1 regulates FOXQ1 gene expression and whether FOXQ1 is essential for FGFR1-stimulated cell proliferation are unknown. Herein, we confirmed that activation of FGFR1 robustly upregulated FOXQ1 mRNA and protein in BC cells. Knockdown of FOXQ1 blocked the FGFR1 signaling-stimulated BC cell proliferation, colony formation, and xenograft tumor growth. Inhibition of MEK or ERK1/2 activities, or knockout of ERK2 but not ERK1 suppressed the FGFR1 signaling-promoted FOXQ1 gene expression. Inhibition of ERK2 in ERK1 knockout cells blocked, while ectopic expression of FOXQ1 in ERK2 knockout cells rescued the FGFR1-signaling-promoted cell growth. Mechanistically, c-FOS, an early response transcription factor upregulated by the FGFR1-MEK-ERK2 pathway, bound to the FOXQ1 promoter to mediate the FGFR1 signaling-promoted FOXQ1 expression. These results indicate that the FGFR1-ERK2-c-FOS-FOXQ1 regulatory axis plays an essential role in the FGFR1 signaling-promoted BC growth. Targeting ERK2 and FOXQ1 should block BC growth caused by a deregulated FGFR1 signaling.© The author(s).