The WAVE3-YB1 interaction regulates cancer stem cells activity in breast cancer.
The WAVE3-YB1 interaction regulates cancer stem cells activity in breast cancer.
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DOI：
10.18632/oncotarget.22009
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发表时间：
2017-11-28
期刊：
影响因子：
--
通讯作者：
Sossey-Alaoui K
中科院分区：
文献类型：
--
作者：
Bledzka K;Schiemann B;Schiemann WP;Fox P;Plow EF;Sossey-Alaoui K
对治疗的抵抗是肿瘤复发和转移的主要原因，并且癌症干细胞（CSCs）在此过程中起着至关重要的作用，特别是在三阴性乳腺癌（TNBC）中。不幸的是，目前没有FDA批准的治疗方法可用于这种BC亚型，这解释了TNBC肿瘤患者的高死亡率。WAVE 3是WASP/WAVE肌动蛋白-细胞骨架重塑蛋白家族的成员，已被确定为几种实体瘤（包括起源于乳腺的实体瘤）的肿瘤进展和转移的主要驱动因素。我们最近发表的研究发现WAVE 3介导了TNBC的化疗耐药性过程。WAVE 3调节TNBC肿瘤中化学抗性的分子机制在很大程度上仍然未知，WAVE 3在CSC维持中的作用也是如此。在这里，我们表明，WAVE 3促进CSC自我更新，并调节CSC特异性基因的转录，这在一定程度上，提供了一个机制解释WAVE 3的功能在TNBC的化疗耐药性。我们的数据显示WAVE 3在TNBC细胞系的CSC亚群中富集。通过CRISPR/Cas9敲除WAVE 3可显着减弱CSC亚群并抑制CSC转录因子的转录。从机制上讲，我们建立了WAVE 3和Y-盒结合蛋白-1（YB 1），转录因子和CSC维持基因之间的联系。事实上，WAVE 3与YB 1的相互作用是YB 1易位到癌细胞核和激活CSC特异性基因转录所必需的。我们的研究结果确定了一个新的WAVE 3/YB 1信号轴，它调节CSC介导的治疗抗性，并为TNBC治疗打开了一个新的治疗窗口。
Resistance to therapy is the main cause of tumor recurrence and metastasis and cancer stem cells (CSCs) play a crucial role in this process, especially in triple-negative breast cancers (TNBCs). Unfortunately, no FDA-approved treatment is currently available for this subtype of BC, which explains the high rate of mortality in patients with TNBC tumors. WAVE3, a member of the WASP/WAVE actin-cytoskeleton remodeling family of protein, has been established as a major driver of tumor progression and metastasis of several solid tumors, including those originating in the breast. Our recently published studies found WAVE3 to mediate the process of chemoresistance in TNBCs. The molecular mechanisms whereby WAVE3 regulates chemoresistance in TNBC tumors remains largely unknown, as does the role of WAVE3 in CSC maintenance. Here we show that WAVE3 promotes CSC self-renewal and regulates transcription of CSC-specific genes, which, in part, provides a mechanistic explanation for the function of WAVE3 in chemoresistance in TNBCs. Our data show that WAVE3 is enriched in the CSC-subpopulation of TNBC cell lines. Knockout of WAVE3 via CRISPR/Cas9 significantly attenuates the CSC-subpopulation and inhibits transcription of CSC transcription factors. Mechanistically, we established a link between WAVE3 and the Y-box-binding protein-1 (YB1), a transcription factor and CSC-maintenance gene. Indeed, the interaction of WAVE3 with YB1 is required for YB1 translocation to the nucleus of cancer cells, and activation of transcription of CSC-specific genes. Our findings identify a new WAVE3/YB1 signaling axis that regulates the CSC-mediated resistance to therapy and opens a new therapeutic window for TNBCs treatment.
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DOI：
10.1158/1541-7786.mcr-11-0311
发表时间：
2011-11
期刊：
Molecular cancer research : MCR
影响因子：
--
作者：
Augoff K;Das M;Bialkowska K;McCue B;Plow EF;Sossey-Alaoui K
通讯作者：
Sossey-Alaoui K
影响因子：
12.3
作者：
Kurisu S;Takenawa T
通讯作者：
Takenawa T
影响因子：
37.3
作者：
Augoff K;McCue B;Plow EF;Sossey-Alaoui K
通讯作者：
Sossey-Alaoui K
影响因子：
11.5
作者：
Fujita, T;Ito, KI;Fujimori, M
通讯作者：
Fujimori, M
影响因子：
10.3
作者：
Lasham, Annette;Samuel, Weini;Braithwaite, Antony W.
通讯作者：
Braithwaite, Antony W.