Oncotarget

Research Papers:

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

Melanie Spitzwieser, Christine Pirker, Bettina Koblmüller, Georg Pfeiler, Stefan Hacker, Walter Berger, Petra Heffeter and Margit Cichna-Markl _

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Oncotarget. 2016; 7:73347-73369. https://doi.org/10.18632/oncotarget.12332

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Abstract

Melanie Spitzwieser1, Christine Pirker2, Bettina Koblmüller2, Georg Pfeiler3, Stefan Hacker4, Walter Berger2, Petra Heffeter2, Margit Cichna-Markl1

1Department of Analytical Chemistry, University of Vienna, Vienna, Austria

2Department of Medicine I, Institute of Cancer Research and Comprehensive Cancer Center of the Medical University, Medical University of Vienna, Vienna, Austria

3Department of Obstetrics and Gynecology, Division of Gynecology and Gynecological Oncology, Medical University of Vienna, Vienna, Austria

4Department of Plastic and Reconstructive Surgery, Medical University of Vienna, Vienna, Austria

Correspondence to:

Margit Cichna-Markl, email: [email protected]

Keywords: ABC transporter, multidrug resistance, DNA methylation, bisulfite pyrosequencing, breast cancer

Received: June 29, 2016     Accepted: September 19, 2016     Published: September 28, 2016

ABSTRACT

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.


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