title: Estrogen Enhances the Expression of the Multidrug Transporter Gene ABCG2-Increasing Drug Resistance of Breast Cancer Cells through Estrogen Receptors.
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.
authors.affiliation: Department of Obstetrics & Gynecology, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan. doc30666@gmail.com.
authors.forename: Fung-Wei
authors.initials: FW
authors.lastname: Chang
authors.affiliation: Department of Pediatrics, Tungs' Taichung MetroHarbor Hospital, Taichung 435, Taiwan. fanhuengchuen@yahoo.com.tw.
authors.forename: Hueng-Chuen
authors.initials: HC
authors.lastname: Fan
authors.affiliation: Division of Urology, Department of Surgery, Taoyuan General Hospital, Ministry of Health and Welfare, Taoyuan 333, Taiwan. mento1218@gmail.com.
authors.forename: Jui-Ming
authors.initials: JM
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, University of Cambridge, Cambridge CB23 8AQ, UK. tpf1000@cam.ac.uk.
authors.forename: Tai-Ping
authors.initials: TP
authors.lastname: Fan
authors.affiliation: Department of Pharmacology, University of Cambridge, Cambridge CB23 8AQ, UK. jinjing1207@hotmail.com.
authors.forename: Jin
authors.initials: J
authors.lastname: Jing
authors.affiliation: Department of Pharmacology, University of Cambridge, Cambridge CB23 8AQ, UK. cly2375@gmail.com.
authors.forename: Chia-Ling
authors.initials: CL
authors.lastname: Yang
authors.affiliation: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 114, Taiwan. hsurnai@gmail.com.|Department of Pathology and Graduate Institute of Pathology and Parasitology, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan. hsurnai@gmail.com.|Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 114, Taiwan. hsurnai@gmail.com.|Biobank Management Center of Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan. hsurnai@gmail.com.
authors.forename: Ren-Jun
authors.initials: RJ
authors.lastname: Hsu
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2 / Q000235:genetics* / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D015687:Cell Hypoxia / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics*; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D050259:Genes, Mitochondrial; D006801:Humans; D061986:MCF-7 Cells; D008954:Models, Biological; D020411:Oligonucleotide Array Sequence Analysis; D017382:Reactive Oxygen Species / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism*
chemical_list: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D004967:Estrogens; D017382:Reactive Oxygen Species; D011960:Receptors, Estrogen; D000255:Adenosine Triphosphate
keywords: ATP-binding cassette sub-family G member 2 (ABCG2); breast cancer; estrogen, estrogen receptor α (ERα); mitoxantrone (MX)