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Increased Nuclear Localization of Transcription Factor Y-Box Binding Protein 1 Accompanied by Up-Regulation of P-glycoprotein in Breast Cancer Pretreated with Paclitaxel

Authors' Affiliations: ¹ Department of Surgery, Shinshu University School of Medicine, Matsumoto, Nagano, Japan; ² Department of Molecular Biology, University of Occupational and Environmental Health, Kitakyushu, Fukuoka, Japan; ³ Department of Surgery, Gunma Prefectural Cancer Center, Ohta, Gunma, Japan; ⁴ Department of Surgery, Niigata Cancer Center Hospital, Niigata, Japan; ⁵ Department of Surgery, Yamanashi Prefectural Central Hospital, Kofu, Yamanashi, Japan; and ⁶ Department of Pathology, Nippon Medical School, Tokyo, Japan

Requests for reprints: Ken-ichi Ito, Department of Surgery, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan. Phone: 81-263-37-2657; Fax: 81-263-37-2721; E-mail: kenito{at}hsp.md.shinshu-u.ac.jp.

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.

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