OBJECTIVES: ATP-Binding Cassette (ABC) transporters may cause treatment failure by transporting of anticancer drugs outside of the tumor cells. Multidrug resistance-associated protein 1 coded by the ABCC1 gene has recently been suggested as a potential prognostic marker in breast cancer patients. This study aimed to explore tagged haplotype covering nucleotide binding domain 1 of ABCC1 in relation with corresponding transcript levels in tissues and clinical phenotype of breast cancer patients. METHODS: The distribution of twelve ABCC1 polymorphisms was assessed by direct sequencing in peripheral blood DNA (n = 540). RESULTS: Tumors from carriers of the wild type genotype in rs35623 or rs35628 exhibited significantly lower levels of ABCC1 transcript than those from carriers of the minor allele (p = 0.003 and p = 0.004, respectively). The ABCC1 transcript levels significantly increased in the order CT-GT>CC-GT>CC-GG for the predicted rs35626-rs4148351 diplotype. Chemotherapy-treated patients carrying the T allele in rs4148353 had longer disease-free survival than those with the GG genotype (p = 0.043). On the other hand, hormonal therapy-treated patients with the AA genotype in rs35628 had significantly longer disease-free survival than carriers of the G allele (p = 0.012). CONCLUSIONS: Taken together, our study shows that genetic variability in the nucleotide binding domain 1 has a significant impact on the ABCC1 transcript level in the target tissue and may modify survival of breast cancer patients.

3rd Faculty of Medicine Charles University Prague Czech Republic

Biolab Praha k s Prague Czech Republic

Department of Oncology Motol University Hospital Prague Czech Republic

Department of Oncology Palacky University Medical School and Teaching Hospital Olomouc Czech Republic

Department of Radiotherapy and Oncology Faculty Hospital Kralovske Vinohrady Prague Czech Republic

Department of Toxicogenomics National Institute of Public Health Prague Czech Republic

Institute for the Care for Mother and Child Prague Czech Republic

Institute of Biology and Medical Genetics 1st Faculty of Medicine Charles University Prague Czech Republic

Institute of Experimental Medicine Czech Academy of Sciences Prague Czech Republic

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$a Kunická, Tereza $u Department of Toxicogenomics, National Institute of Public Health, Prague, Czech Republic; 3rd Faculty of Medicine, Charles University, Prague, Czech Republic.

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$a Non-coding polymorphisms in nucleotide binding domain 1 in ABCC1 gene associate with transcript level and survival of patients with breast cancer / $c T. Kunická, R. Václavíková, V. Hlaváč, D. Vrána, V. Pecha, K. Rauš, M. Trnková, K. Kubáčková, M. Ambruš, L. Vodičková, P. Vodička, P. Souček,

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$a OBJECTIVES: ATP-Binding Cassette (ABC) transporters may cause treatment failure by transporting of anticancer drugs outside of the tumor cells. Multidrug resistance-associated protein 1 coded by the ABCC1 gene has recently been suggested as a potential prognostic marker in breast cancer patients. This study aimed to explore tagged haplotype covering nucleotide binding domain 1 of ABCC1 in relation with corresponding transcript levels in tissues and clinical phenotype of breast cancer patients. METHODS: The distribution of twelve ABCC1 polymorphisms was assessed by direct sequencing in peripheral blood DNA (n = 540). RESULTS: Tumors from carriers of the wild type genotype in rs35623 or rs35628 exhibited significantly lower levels of ABCC1 transcript than those from carriers of the minor allele (p = 0.003 and p = 0.004, respectively). The ABCC1 transcript levels significantly increased in the order CT-GT>CC-GT>CC-GG for the predicted rs35626-rs4148351 diplotype. Chemotherapy-treated patients carrying the T allele in rs4148353 had longer disease-free survival than those with the GG genotype (p = 0.043). On the other hand, hormonal therapy-treated patients with the AA genotype in rs35628 had significantly longer disease-free survival than carriers of the G allele (p = 0.012). CONCLUSIONS: Taken together, our study shows that genetic variability in the nucleotide binding domain 1 has a significant impact on the ABCC1 transcript level in the target tissue and may modify survival of breast cancer patients.

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$a Hlaváč, Viktor $u Department of Toxicogenomics, National Institute of Public Health, Prague, Czech Republic; 3rd Faculty of Medicine, Charles University, Prague, Czech Republic. $7 xx0270481

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$a Vrána, David $u Department of Toxicogenomics, National Institute of Public Health, Prague, Czech Republic; Department of Oncology, Palacky University Medical School and Teaching Hospital, Olomouc, Czech Republic. $7 xx0103187

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