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首页> 外文期刊>Breast Cancer Research >Epidermal growth factor receptor (EGFR) is transcriptionally induced by the Y-box binding protein-1 (YB-1) and can be inhibited with Iressa in basal-like breast cancer, providing a potential target for therapy
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Epidermal growth factor receptor (EGFR) is transcriptionally induced by the Y-box binding protein-1 (YB-1) and can be inhibited with Iressa in basal-like breast cancer, providing a potential target for therapy

机译：表皮生长因子受体（EGFR）由Y-box结合蛋白1（YB-1）转录诱导，在基底样乳腺癌中可以被易瑞沙抑制，为治疗提供了潜在靶点

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IntroductionBasal-like breast cancers (BLBCs) are very aggressive, and present serious clinical challenges as there are currently no targeted therapies available. We determined the regulatory role of Y-box binding protein-1 (YB-1) on epidermal growth factor receptor (EGFR) overexpression in BLBC, and the therapeutic potential of inhibiting EGFR. We pursued this in light of our recent work showing that YB-1 induces the expression of EGFR, a new BLBC marker.MethodsPrimary tumour tissues were evaluated for YB1 protein expression by immunostaining tissue microarrays, while copy number changes were assessed by comparative genomic hybridization (CGH). The ability of YB-1 to regulate EGFR was evaluated using luciferase reporter, chromatin immunoprecipitation (ChIP) and gel shift assays. The impact of Iressa on monolayer cell growth was measured using an ArrayScan VTI high-throughput analyser to count cell number, and colony formation in soft agar was used to measure anchorage-independent growth.ResultsYB-1 (27/37 or 73% of cases, P = 3.899 × 10-4) and EGFR (20/37 or 57.1% of cases, P = 9.206 × 10-12) are expressed in most cases of BLBC. However, they are not typically amplified in primary BLBC, suggesting overexpression owing to transcriptional activation. In support of this, we demonstrate that YB-1 promotes EGFR reporter activity. YB-1 specifically binds the EGFR promoter at two different YB-1-responsive elements (YREs) located at -940 and -968 using ChIP and gel shift assays in a manner that is dependent on the phosphorylation of S102 on YB-1. Inhibiting EGFR with Iressa suppressed the growth of SUM149 cells by ~40% in monolayer, independent of mutations in the receptor. More importantly anchorage-independent growth of BLBC cell lines was inhibited with combinations of Iressa and YB-1 suppression.ConclusionWe have identified for the first time a causal link for the expression of EGFR in BLBC through the induction by YB-1 where it binds specifically to two distinguished YREs. Finally, inhibition of EGFR in combination with suppression of YB-1 presents a potential opportunity for therapy in BLBC.
机译：简介基底样乳腺癌（BLBCs）具有非常强的侵袭性，并且由于目前没有针对性的治疗方法，因此也面临着严峻的临床挑战。我们确定了Y盒结合蛋白1（YB-1）对BLBC中表皮生长因子受体（EGFR）过表达的调节作用，以及抑制EGFR的治疗潜力。我们根据最近的研究表明YB-1诱导了一种新的BLBC标记EGFR的表达来进行研究。方法通过免疫染色组织微阵列评估原发性肿瘤组织中YB1蛋白的表达，同时通过比较基因组杂交评估拷贝数的变化（ CGH）。使用荧光素酶报道分子，染色质免疫沉淀（ChIP）和凝胶位移分析法评估YB-1调节EGFR的能力。使用ArrayScan VTI高通量分析仪测量易瑞沙对单层细胞生长的影响以计算细胞数量，并使用软琼脂中的菌落形成来测量不依赖锚定的生长。结果YB-1（27/37或73％的病例，P = 3.899×10-4）和EGFR（20/37或57.1％的病例，P = 9.206×10-12）在大多数BLBC病例中均有表达。但是，它们通常不会在原代BLBC中扩增，提示由于转录激活而导致过表达。为此，我们证明了YB-1可以促进EGFR报告基因活性。使用ChIP和凝胶位移测定法，YB-1以依赖于YB-1上S102磷酸化的方式特异性地将EGFR启动子结合在位于-940和-968的两个不同的YB-1反应元件（YRE）上。用易瑞沙（Ireessa）抑制EGFR可单层抑制SUM149细胞的生长约40％，而与受体突变无关。更重要的是，易瑞沙和YB-1抑制组合抑制了不依赖于锚定的BLBC细胞系的生长。结论我们首次确定了YBC-1诱导BLBC中EGFR表达的因果关系，其中它与BBC特异性结合到两个杰出的YRE。最后，EGFR的抑制与YB-1的抑制相结合为BLBC的治疗提供了潜在的机会。

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