Increased nuclear localization of transcription factor Y-box binding protein 1 accompanied by up-regulation of P-glycoprotein in breast cancer pretreated with paclitaxel.
Increased nuclear localization of transcription factor Y-box binding protein 1 accompanied by up-regulation of P-glycoprotein in breast cancer pretreated with paclitaxel.
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DOI：
10.1158/0008-5472.sabcs-09-1141
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发表时间：
2009-12
期刊：
影响因子：
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通讯作者：
Tomoyuki Fujita;Ken-ichi Ito;H. Izumi;M. Kimura;M. Sano;H. Nakagomi;K. Maeno;Y. Hama;K. Shingū;S. Tsuchiya;K. Kohno;M. Fujimori
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文献类型：
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作者：
Tomoyuki Fujita;Ken-ichi Ito;H. Izumi;M. Kimura;M. Sano;H. Nakagomi;K. Maeno;Y. Hama;K. Shingū;S. Tsuchiya;K. Kohno;M. Fujimori
目的Y-box结合蛋白1(YB-1)调节mdr1基因编码的P-糖蛋白的表达。以前还没有关于YB-1参与紫杉醇耐药的研究。本研究旨在探讨紫杉醇如何影响YB-1在乳腺癌中的定位和表达。实验设计研究紫杉醇治疗前后27例乳腺癌组织中YB-1和P-糖蛋白的表达和定位。用GFP-YB-1检测紫杉醇对YB-1细胞定位的影响。用凝胶迁移率改变分析法研究了YB-1与MDR1启动子的Y盒基序的相互作用。用荧光素酶分析法检测紫杉醇对mdr1启动子活性的影响。结果紫杉醇治疗的27例乳腺癌组织中，9例(33%)在治疗过程中发现YB-1由胞浆移位至胞核，并伴有P-糖蛋白表达增加。12例乳腺癌组织(44%)未见YB-1易位或P-糖蛋白表达增加。YB-1的核转位与P-糖蛋白的表达显著相关(P=0.0037)。共聚焦分析表明，紫杉醇可诱导MCF7细胞绿色荧光融合基因YB-1的核转位。此外，紫杉醇处理后，YB-1与mdr1启动子Y盒的结合增加。此外，紫杉醇显著上调mdr1启动子活性(P<；0.001)。结论YB-1基因可能参与了乳腺癌紫杉醇耐药的形成。
PURPOSE The Y-box binding protein 1 (YB-1) regulates expression of P-glycoprotein encoded by the MDR1 gene. There have been no previous studies regarding the involvement of YB-1 in the development of resistance to paclitaxel. The present study was done to examine how paclitaxel affects the localization and expression of YB-1 in breast cancer. EXPERIMENTAL DESIGN We evaluated the expression and localization of YB-1 and P-glycoprotein in breast cancer tissues obtained from 27 patients before and after treatment with paclitaxel. The effect of paclitaxel on localization of cellular YB-1 was examined by using GFP-YB-1. Interaction of YB-1 with the Y-box motif of the MDR1 promoters was studied by electrophoretic mobility shift assay. The effects of paclitaxel on MDR1 promoter activity were examined by luciferase assay. RESULTS Of 27 breast cancer tissues treated with paclitaxel, nine (33%) showed translocation of YB-1 from the cytoplasm to the nucleus together with increased expression of P-glycoprotein during the course of treatment. Twelve breast cancer tissues (44%) showed neither translocation of YB-1 nor increased expression of P-glycoprotein. Nuclear translocation of YB-1 was correlated significantly with increased expression of P-glycoprotein (P=0.0037). Confocal analysis indicated that paclitaxel induced nuclear translocation of green fluorescent fused YB-1 in MCF7 cells. Furthermore, binding of YB-1 to the Y-box of MDR1 promoter was increased in response to treatment with paclitaxel. In addition, MDR1 promoter activity was significantly up-regulated by paclitaxel in MCF7 cells (P<0.001). CONCLUSIONS The results of the present study suggested that YB-1 may be involved in the development of resistance to paclitaxel in breast cancer.