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Analysis of predictive factors for chemotherapeutic response in breast cancer by using histoculture drug response assay and immunohistochemistry.

使用组织培养药物反应测定和免疫组织化学分析乳腺癌化疗反应的预测因素。

基本信息

批准号：
17591325
负责人：
ITO Ken-ichi
金额：
$ 2.24万
依托单位：
Shinshu University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17591325/
关键词：
Breast cancer Chemotherapeutic sensitivity Mechanisms of drug resistance Transcription factor

项目摘要

Research 1 Increased Nuclear Localization of Transcription Factor Y-Box Binding Protein 1 Accompanied by Up-Regulation of P-glycoprotein in Breast Cancer Pretreated with PaclitaxelPurpose : The Y-box binding protein 1 (YB-1) regulates expression of P-glycoprotein encoded by the MDR1 gene. 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 promoter s 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 … More 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. 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.Research 2 Analysis of predictive factors for chemotherapeutic response in breast cancer by using histoculture drug response assay and immunohistochemistry.Purpose : The purpose of this study is to find predictive factors evaluated by IHC for the response of anticancer drugs in the patients with clinical breast cancer.Patients and Methods : Breast cancer tissues were obtained from 60 patients with primary breast cancer, and histoculture drug response assays (HDRA) for epirubicine, paclitaxel, 5FU, and cyclophosphamide were performed. The expressions of 13 molecular markers (ER, PgR, Her2, Topo IIα, P-glycoprotein, p53,MRP1, BCRP, Ki-67, YB-1, GRP67, Bcl-2, c-Myc) were evaluated by IHC. We compared the results of the expression of molecular markers and the sensitivity to anticancer drugs measured by HDRA.Results : The sensitivity to epirubicine was significantly higher in Ki-67 positive/p53 positive/low Bcl-2 tumors. As for the sensitivity to paclitaxel, the tumors which showed Ki-67 positive/Topo IIα positive or Ki-67 positive/low P-gp demonstrated significantly higher sensitivity. The sensitivity to 5FU was significantly increased in Ki-67 positive/low Bcl-2 tumors.Conclusions : The combination of several molecular markers evaluated by IHC might be useful in prediction of sensitivity of individual breast cancers to anticancer drugs evaluated by HDRA. Less

研究 1 在紫杉醇预处理的乳腺癌中，转录因子 Y 盒结合蛋白 1 的核定位增加，同时 P 糖蛋白上调目的：Y 盒结合蛋白 1 (YB-1) 调节 MDR1 基因编码的 P 糖蛋白的表达。本研究旨在探讨紫杉醇如何影响乳腺癌中 YB-1 的定位和表达。实验设计：我们评估了紫杉醇治疗前后 27 名患者的乳腺癌组织中 YB-1 和 P-糖蛋白的表达和定位。使用GFP-YB-1检查紫杉醇对细胞YB-1定位的影响。通过电泳迁移率变动分析研究了 YB-1 与 MDR1 启动子的 Y-box 基序的相互作用。通过荧光素酶测定检查紫杉醇对 MDR1 启动子活性的影响。结果：在接受紫杉醇治疗的 27 个乳腺癌组织中，有 9 个 (33%) 在治疗过程中显示 YB-1 从细胞质易位到细胞核，同时 P-糖蛋白表达增加。 12 个乳腺癌组织 (44%) 既没有显示 YB-1 易位，也没有显示 P-糖蛋白表达增加。 YB-1 的核转位与 P-糖蛋白表达的增加显着相关。共聚焦分析表明紫杉醇诱导MCF7细胞中绿色荧光融合YB-1的核转位。此外，YB-1 与 MDR1 启动子 Y 盒的结合因紫杉醇治疗而增加。此外，MCF7细胞中紫杉醇显着上调MDR1启动子活性（P < 0.001）。结论：本研究结果提示YB-1可能参与了乳腺癌紫杉醇耐药的发生。研究2通过组织培养药物反应试验和免疫组化分析乳腺癌化疗反应的预测因素。目的：本研究的目的目的是寻找通过 IHC 评估临床乳腺癌患者抗癌药物反应的预测因素。患者和方法：从 60 名原发性乳腺癌患者中获取乳腺癌组织，对表柔比星、紫杉醇、5FU 和环磷酰胺进行组织培养药物反应测定 (HDRA)。 IHC检测13个分子标志物（ER、PgR、Her2、Topo IIα、P-糖蛋白、p53、MRP1、BCRP、Ki-67、YB-1、GRP67、Bcl-2、c-Myc）的表达。我们比较了分子标志物的表达结果和HDRA测得的抗癌药物敏感性。结果：Ki-67阳性/p53阳性/低Bcl-2肿瘤对表柔比星的敏感性显着较高。对于紫杉醇的敏感性，Ki-67阳性/Topo IIα阳性或Ki-67阳性/低P-gp的肿瘤表现出明显更高的敏感性。 Ki-67 阳性/低 Bcl-2 肿瘤中对 5FU 的敏感性显着增加。结论：通过 IHC 评估的几种分子标记的组合可能有助于预测个体乳腺癌对通过 HDRA 评估的抗癌药物的敏感性。较少的