Increased nuclear localization of transcription factor Y-box binding protein 1 accompanied by up-regulation of P-glycoprotein in breast cancer pretreated with paclitaxel.

Abstract

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.

• Authors: Tomoyuki Fujita, Ken-ichi Ito, Hiroto Izumi, Morihiko Kimura, Muneaki Sano, Hiroshi Nakagomi, Kazuma Maeno, Yoshihisa Hama, Kiyoshi Shingu, Shin-ichi Tsuchiya, Kimitoshi Kohno, Minoru Fujimori
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 11 Issue 24 Pt 1 Pg. 8837-44 (Dec 15 2005) ISSN: 1078-0432 [Print] United States
• PMID: 16361573 (Publication Type: Journal Article)

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Antineoplastic Agents, Phytogenic
• Y-Box-Binding Protein 1
• Paclitaxel

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (genetics, metabolism)
• Active Transport, Cell Nucleus (drug effects)
• Antineoplastic Agents, Phytogenic (pharmacology, therapeutic use)
• Breast Neoplasms (chemistry, drug therapy, metabolism)
• Cell Nucleus (chemistry, metabolism)
• Drug Resistance, Neoplasm (genetics)
• Female
• Gene Expression Regulation
• Humans
• Immunohistochemistry
• Paclitaxel (pharmacology, therapeutic use)
• Promoter Regions, Genetic
• Tumor Cells, Cultured
• Up-Regulation
• Y-Box-Binding Protein 1 (analysis, metabolism)