Wnt signaling blockage inhibits cell proliferation and migration, and induces apoptosis in triple-negative breast cancer cells.
Wnt signaling blockage inhibits cell proliferation and migration, and induces apoptosis in triple-negative breast cancer cells.
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DOI：
10.1186/1479-5876-11-280
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发表时间：
2013-11-04
影响因子：
7.4
通讯作者：
Moreno CS
中科院分区：
文献类型：
--
作者：
Bilir B;Kucuk O;Moreno CS
三阴性乳腺癌（TNBC）是乳腺癌的侵袭性临床亚型，其特征在于缺乏雌激素受体（ER）和孕激素受体（PR）表达以及人表皮生长因子受体2（HER 2）过表达。TNBC亚型占所有乳腺癌的约10%-20%，但没有有效的分子靶向治疗。先前对来自21项研究的587例TNBC病例的基因表达谱进行的荟萃分析表明，Wnt信号通路相关基因在TNBC的基底细胞样2和间充质亚型中高表达。在这项研究中，我们研究了Wnt通路抑制剂在有效治疗TNBC中的潜力。在四种TNBC细胞系（BT-549、MDA-MB-231、HCC-1143和HCC-1937）和ER+细胞系MCF-7中使用共聚焦显微镜和途径组分的蛋白质印迹分析评估Wnt途径的活化。在体外测试了五种不同的Wnt途径抑制剂（iCRT-3、iCRT-5、iCRT-14、IWP-4和XAV-939）对细胞增殖和凋亡的有效性。通过Axin 2的定量实时RT-PCR分析和双荧光素酶报告基因测定来评估iCRT-3对TNBC中典型Wnt信号传导的抑制作用。还评估了S 0X 4的shRNA敲低与iCRT-3和/或染料木黄酮处理组合对BT-549细胞上的细胞增殖、迁移和侵袭的影响。TNBC细胞系中β-连环蛋白的免疫荧光染色显示出细胞核和细胞质定位，表明TNBC细胞中Wnt途径的激活。iCRT-3是抑制TNBC细胞增殖和拮抗Wnt信号传导的最有效化合物。此外，用iCRT-3处理导致体外细胞凋亡增加。三阴性BT-549细胞中Wnt途径转录因子SOX 4的敲低导致细胞增殖和迁移降低，iCRT-3与SOX 4敲低的联合处理对细胞增殖抑制和细胞凋亡诱导具有协同作用。这些数据表明，靶向S 0X 4和/或Wnt通路可能对TNBC患者具有治疗益处。
Triple-negative breast cancer (TNBC) is an aggressive clinical subtype of breast cancer that is characterized by the lack of estrogen receptor (ER) and progesterone receptor (PR) expression as well as human epidermal growth factor receptor 2 (HER2) overexpression. The TNBC subtype constitutes approximately 10%–20% of all breast cancers, but has no effective molecular targeted therapies. Previous meta-analysis of gene expression profiles of 587 TNBC cases from 21 studies demonstrated high expression of Wnt signaling pathway-associated genes in basal-like 2 and mesenchymal subtypes of TNBC. In this study, we investigated the potential of Wnt pathway inhibitors in effective treatment of TNBC. Activation of Wnt pathway was assessed in four TNBC cell lines (BT-549, MDA-MB-231, HCC-1143 and HCC-1937), and the ER+ cell line MCF-7 using confocal microscopy and Western blot analysis of pathway components. Effectiveness of five different Wnt pathway inhibitors (iCRT-3, iCRT-5, iCRT-14, IWP-4 and XAV-939) on cell proliferation and apoptosis were tested in vitro. The inhibitory effects of iCRT-3 on canonical Wnt signaling in TNBC was evaluated by quantitative real-time RT-PCR analysis of Axin2 and dual-luciferase reporter assays. The effects of shRNA knockdown of SOX4 in combination with iCRT-3 and/or genistein treatments on cell proliferation, migration and invasion on BT-549 cells were also evaluated. Immunofluorescence staining of β-catenin in TNBC cell lines showed both nuclear and cytoplasmic localization, indicating activation of Wnt pathway in TNBC cells. iCRT-3 was the most effective compound for inhibiting proliferation and antagonizing Wnt signaling in TNBC cells. In addition, treatment with iCRT-3 resulted in increased apoptosis in vitro. Knockdown of the Wnt pathway transcription factor, SOX4 in triple negative BT-549 cells resulted in decreased cell proliferation and migration, and combination treatment of iCRT-3 with SOX4 knockdown had a synergistic effect on inhibition of cell proliferation and induction of apoptosis. These data suggest that targeting SOX4 and/or the Wnt pathway could have therapeutic benefit for TNBC patients.
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影响因子：
11.5
作者：
Hoeflich, Klaus P.;O'Brien, Carol;Lackner, Mark R.
通讯作者：
Lackner, Mark R.
影响因子：
4.2
作者：
Lee, Ae-Kyung;Ahn, Sang-Gun;Kim, Soo-A
通讯作者：
Kim, Soo-A
影响因子：
11.2
作者：
Scharer, Christopher D.;McCabe, Colleen D.;Ali-Seyed, Mohamed;Berger, Michael F.;Bulyk, Martha L.;Moreno, Carlos S.
通讯作者：
Moreno, Carlos S.
影响因子：
14.8
作者：
Chen, Baozhi;Dodge, Michael E.;Tang, Wei;Lu, Jianming;Ma, Zhiqiang;Fan, Chih-Wei;Wei, Shuguang;Hao, Wayne;Kilgore, Jessica;Williams, Noelle S.;Roth, Michael G.;Amatruda, James F.;Chen, Chuo;Lum, Lawrence
通讯作者：
Lum, Lawrence
影响因子：
11.5
作者：
Rakha, Emad A.;Elsheikh, Somaia E.;Ellis, Ian O.
通讯作者：
Ellis, Ian O.