FOXC1 is a critical mediator of EGFR function in human basal-like breast cancer.
FOXC1 is a critical mediator of EGFR function in human basal-like breast cancer.
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DOI：
10.1245/s10434-014-3980-3
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发表时间：
2014-12
影响因子：
3.7
通讯作者：
Cui X
中科院分区：
文献类型：
--
作者：
Jin Y;Han B;Chen J;Wiedemeyer R;Orsulic S;Bose S;Zhang X;Karlan BY;Giuliano AE;Cui Y;Cui X
人基底细胞样乳腺癌（BLBC）预后差，通常通过表皮生长因子受体（EGFR）的表达来鉴定。BLBC仍然是一个主要的临床挑战，因为它的发病机制还没有得到很好的理解，从而阻碍了开发靶向治疗的努力。最近的研究表明，FOXC 1转录因子是BLBC重要的预后生物标志物和功能调节因子，但其调控机制和对BLBC肿瘤发生的影响尚不清楚。通过福尔马林固定组织的免疫组化和TCGA数据库分析，研究FOXC 1和EGFR在人乳腺癌中表达的相关性。使用免疫印迹、qRT-PCR和荧光素酶活性测定在MDA-MB-468细胞中研究EGFR激活对FOXC 1的调节。使用MDA-MB-468异种移植模型证实了EGFR对FOXC 1表达的这种作用。FOXC 1 mRNA和蛋白水平与EGFR在乳腺肿瘤中的表达显著相关。EGFR激活通过ERK和Akt途径诱导BLBC中FOXC 1的转录。体内EGFR抑制降低了异种移植肿瘤中FOXC 1的表达。我们还发现，FOXC 1敲低削弱了EGF对BLBC细胞增殖，迁移和侵袭的影响。我们的研究结果揭示了一种新的EGFR-FOXC 1信号轴对BLBC细胞功能至关重要，支持FOXC 1通路的干预可能为BLBC治疗提供潜在模式的观点。
Human basal-like breast cancer (BLBC) has a poor prognosis and is often identified by expression of the epidermal growth factor receptor (EGFR). BLBC remains a major clinical challenge because its pathogenesis is not well understood, thus hindering efforts to develop targeted therapies. Recent data implicate the forkhead box C1 (FOXC1) transcription factor as an important prognostic biomarker and functional regulator of BLBC, but its regulatory mechanism and impact on BLBC tumorigenesis remain unclear. The association between FOXC1 and EGFR expression in human breast cancer was examined by immunohistochemistry in formalin-fixed tissues and analysis of the TCGA database. The regulation of FOXC1 by EGFR activation was investigated in MDA-MB-468 cells using immunoblotting, qRT-PCR, and luciferase activity assays. This EGFR effect on FOXC1 expression was confirmed using the MDA-MB-468 xenograft model. Both FOXC1 mRNA and protein levels significantly correlated with EGFR expression in human breast tumors. EGFR activation induced FOXC1 transcription through the ERK and Akt pathways in BLBC. EGFR inhibition in vivo reduced FOXC1 expression in xenograft tumors. We also found that FOXC1 knockdown impaired the effects of EGF on BLBC cell proliferation, migration, and invasion. Our findings uncover a novel EGFR-FOXC1 signaling axis critical for BLBC cell functions, supporting the notion that intervention in the FOXC1 pathway may provide potential modalities for BLBC treatment.
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