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：
10.1158/1078-0432.ccr-05-0945
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发表时间：
2005-12-15
影响因子：
11.5
通讯作者：
Fujimori, M
中科院分区：
文献类型：
--
作者：
Fujita, T;Ito, KI;Fujimori, M
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对YB-1在乳腺癌组织中定位和表达的影响。实验设计：评价27例乳腺癌患者紫杉醇治疗前后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。结果：在紫杉醇治疗的27例乳腺癌组织中，有9例(33%)出现YB-1从胞浆转位到胞核，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。另外，紫杉醇显著上调MCF7细胞mdr1启动子活性(P<；0.001)。结论：YB-1基因可能参与了乳腺癌对紫杉醇耐药的形成。
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.