Promoter methylation patterns of ABCB1, ABCC1 and ABCG2 in human cancer cell lines, multidrug-resistant cell models and tumor, tumor-adjacent and tumor-distant tissues from breast cancer patients.
Overexpression of ABCB1, ABCC1 and ABCG2 in tumor tissues is considered a major cause of limited efficacy of anticancer drugs. Gene expression of ABC transporters is regulated by multiple mechanisms, including changes in the DNA methylation status. Most of the studies published so far only report promoter methylation levels for either ABCB1 or ABCG2, and data on the methylation status for ABCC1 are scarce. Thus, we determined the promoter methylation patterns of ABCB1, ABCC1 and ABCG2 in 19 human cancer cell lines. In order to contribute to the elucidation of the role of DNA methylation changes in acquisition of a multidrug resistant (MDR) phenotype, we also analyzed the promoter methylation patterns in drug-resistant sublines of the cancer cell lines GLC-4, SW1573, KB-3-1 and HL-60. In addition, we investigated if aberrant promoter methylation levels of ABCB1, ABCC1 and ABCG2 occur in tumor and tumor-surrounding tissues from breast cancer patients.Our data indicates that hypomethylation of the ABCC1 promoter is not cancer type-specific but occurs in cancer cell lines of different origins. Promoter methylation was found to be an important mechanism in gene regulation of ABCB1 in parental cancer cell lines and their drug-resistant sublines. Overexpression of ABCC1 in MDR cell models turned out to be mediated by gene amplification, not by changes in the promoter methylation status of ABCC1. In contrast to the promoters of ABCC1 and ABCG2, the promoter of ABCB1 was significantly higher methylated in tumor tissues than in tumor-adjacent and tumor-distant tissues from breast cancer patients.
Department of Analytical Chemistry, University of Vienna, Vienna, Austria.
Melanie
M
Spitzwieser
Department of Medicine I, Institute of Cancer Research and Comprehensive Cancer Center of the Medical University, Medical University of Vienna, Vienna, Austria.
Christine
C
Pirker
Department of Medicine I, Institute of Cancer Research and Comprehensive Cancer Center of the Medical University, Medical University of Vienna, Vienna, Austria.
Bettina
B
Koblmüller
Department of Obstetrics and Gynecology, Division of Gynecology and Gynecological Oncology, Medical University of Vienna, Vienna, Austria.
Georg
G
Pfeiler
Department of Plastic and Reconstructive Surgery, Medical University of Vienna, Vienna, Austria.
Stefan
S
Hacker
Department of Medicine I, Institute of Cancer Research and Comprehensive Cancer Center of the Medical University, Medical University of Vienna, Vienna, Austria.
Walter
W
Berger
Department of Medicine I, Institute of Cancer Research and Comprehensive Cancer Center of the Medical University, Medical University of Vienna, Vienna, Austria.
Petra
P
Heffeter
Department of Analytical Chemistry, University of Vienna, Vienna, Austria.
Margit
M
Cichna-Markl
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2 / Q000235:genetics*; D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D018899:CpG Islands; D056915:DNA Copy Number Variations; D019175:DNA Methylation; D018432:Drug Resistance, Multiple / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D006801:Humans; D008875:Middle Aged; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics*; D000071184:Pharmacogenomic Variants; D011401:Promoter Regions, Genetic; D015203:Reproducibility of Results; D017422:Sequence Analysis, DNA
D018435:ATP Binding Cassette Transporter, Subfamily B; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; C513055:ABCB1 protein, human; C116614:ABCG2 protein, human; C421109:multidrug resistance-associated protein 1
ABC transporter; DNA methylation; bisulfite pyrosequencing; breast cancer; multidrug resistance
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