Chung Stacey, Jin Yanli, Han Bingchen, Qu Ying, Gao Bowen, Giuliano Armando E, Cui Xiaojiang
Department of Surgery, Samuel Oschin Cancer Institute, Cedars-Sinai Medical Center, California, Los Angeles, 90048, USA.
Cedars-Sinai Medical Center, Davis Research Building 2065, 8700 Beverly Blvd, California, Los Angeles, 90048, USA.
Cell Commun Signal. 2017 Jun 19;15(1):22. doi: 10.1186/s12964-017-0180-3.
The pathogenesis of human basal-like breast cancer (BLBC) is not well understood and patients with BLBC have a poor prognosis. Expression of the epidermal growth factor receptor (EGFR) and nuclear factor-κB (NF-κB) is well-known to be upregulated in BLBC. The forkhead box C1 (FOXC1) transcription factor, an important prognostic biomarker specific for BLBC, has been shown to be induced by EGF and is critical for EGF effects in breast cancer cells. How FOXC1 is transcriptionally activated in BLBC is not clear.
Luciferase reporter assays were performed to show that NF-κB-p65 enhances FOXC1 promoter activity in BLBC cells (MDA-MB-468). Electrophoretic mobility shift assay, biotinylated oligonucleotide precipitation assay, and chromatin immunoprecipitation assay were used to show that NF-κB interacts and binds to the promoter region of FOXC1.
In this study, we demonstrate that NF-κB is a pivotal mediator of the EGF/EGFR regulation of FOXC1 expression by binding to the FOXC1 promoter to activate FOXC1 transcription. Loss or inhibition of NF-κB diminished FOXC1 expression.
Collectively, our findings reveal a novel EGFR-NF-κB-FOXC1 signaling axis that is critical for BLBC cell function, supporting the notion that intervention in the FOXC1 pathway may provide potential modalities for BLBC treatment.
人类基底样乳腺癌（BLBC）的发病机制尚未完全明确，且BLBC患者预后较差。众所周知，表皮生长因子受体（EGFR）和核因子-κB（NF-κB）在BLBC中表达上调。叉头框C1（FOXC1）转录因子是BLBC特有的重要预后生物标志物，已被证明可被表皮生长因子（EGF）诱导，并且对乳腺癌细胞中的EGF效应至关重要。FOXC1在BLBC中如何被转录激活尚不清楚。
进行荧光素酶报告基因检测以表明NF-κB-p65增强BLBC细胞（MDA-MB-468）中FOXC1启动子活性。采用电泳迁移率变动分析、生物素化寡核苷酸沉淀分析和染色质免疫沉淀分析来表明NF-κB与FOXC1的启动子区域相互作用并结合。
在本研究中，我们证明NF-κB通过与FOXC1启动子结合以激活FOXC1转录，是EGF/EGFR调节FOXC1表达的关键介质。NF-κB的缺失或抑制会降低FOXC1的表达。
总体而言，我们的研究结果揭示了一种新的EGFR-NF-κB-FOXC1信号轴，该信号轴对BLBC细胞功能至关重要，支持了干预FOXC1途径可能为BLBC治疗提供潜在方式的观点。
