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Int. J. Mol. Sci. 2017, 18(1), 163; doi:10.3390/ijms18010163

Estrogen Enhances the Expression of the Multidrug Transporter Gene ABCG2—Increasing Drug Resistance of Breast Cancer Cells through Estrogen Receptors

1
Department of Obstetrics & Gynecology, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan
2
Department of Pediatrics, Tungs’ Taichung MetroHarbor Hospital, Taichung 435, Taiwan
3
Division of Urology, Department of Surgery, Taoyuan General Hospital, Ministry of Health and Welfare, Taoyuan 333, Taiwan
4
Department of Pharmacology, University of Cambridge, Cambridge CB23 8AQ, UK
5
Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 114, Taiwan
6
Department of Pathology and Graduate Institute of Pathology and Parasitology, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan
7
Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 114, Taiwan
8
Biobank Management Center of Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan
*
Author to whom correspondence should be addressed.
Academic Editor: William Chi-shing Cho
Received: 14 October 2016 / Revised: 6 January 2017 / Accepted: 6 January 2017 / Published: 14 January 2017
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Abstract

Background: Multidrug resistance is a major obstacle in the successful therapy of breast cancer. Studies have proved that this kind of drug resistance happens in both human cancers and cultured cancer cell lines. Understanding the molecular mechanisms of drug resistance is important for the reasonable design and use of new treatment strategies to effectively confront cancers. Results: In our study, ATP-binding cassette sub-family G member 2 (ABCG2), adenosine triphosphate (ATP) synthase and cytochrome c oxidase subunit VIc (COX6C) were over-expressed more in the MCF-7/MX cell line than in the normal MCF7 cell line. Therefore, we believe that these three genes increase the tolerance of MCF7 to mitoxantrone (MX). The data showed that the high expression of COX6C made MCF-7/MX have more stable on mitochondrial membrane potential (MMP) and reactive oxygen species (ROS) expression than normal MCF7 cells under hypoxic conditions. The accumulation of MX was greater in the ATP-depleted treatment MCF7/MX cells than in normal MCF7/MX cells. Furthermore, E2 increased the tolerance of MCF7 cells to MX through inducing the expression of ABCG2. However, E2 could not increase the expression of ABCG2 after the inhibition of estrogen receptor α (ERα) in MCF7 cells. According to the above data, under the E2 treatment, MDA-MB231, which lacks ER, had a higher sensitivity to MX than MCF7 cells. Conclusions: E2 induced the expression of ABCG2 through ERα and the over-expressed ABCG2 made MCF7 more tolerant to MX. Moreover, the over-expressed ATP synthase and COX6c affected mitochondrial genes and function causing the over-expressed ABCG2 cells pumped out MX in a concentration gradient from the cell matrix. Finally lead to chemoresistance. View Full-Text
Keywords: breast cancer; mitoxantrone (MX); ATP-binding cassette sub-family G member 2 (ABCG2); estrogen, estrogen receptor α (ERα) breast cancer; mitoxantrone (MX); ATP-binding cassette sub-family G member 2 (ABCG2); estrogen, estrogen receptor α (ERα)
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MDPI and ACS Style

Chang, F.-W.; Fan, H.-C.; Liu, J.-M.; Fan, T.-P.; Jing, J.; Yang, C.-L.; Hsu, R.-J. Estrogen Enhances the Expression of the Multidrug Transporter Gene ABCG2—Increasing Drug Resistance of Breast Cancer Cells through Estrogen Receptors. Int. J. Mol. Sci. 2017, 18, 163.

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