| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2006: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 2005: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Research Abstract |
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 Paclitaxel
Purpose : 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
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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
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