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       35. The role of multidrug resistance gene 1 (MDR1) in breast cancer resistance

      R. Vaclavikova1, S. Nordgard2, GA Alnaes2, M. Hubackova1, E. Kubala3, R. Kodet3,
              M. Mrhalova3, J. Novotny4, VN Kristensen2, I. Gut1 and P. Soucek1
                  National Institute of Public Health, Prague, Czech Republic;
             Department of Genetics, Institute for Cancer Research, Oslo, Norway;
       Department of Pathology and Molecular Medicine, 2nd Faculty of Medicine, Charles
                             University, Prague, Czech Republic;
    Department of Oncology, General Teaching Hospital and 1st Faculty of Medicine, Charles
                              University, Prague, Czech Republic


Multidrug resistance of tumor cells to cytotoxic drugs is one of the major impediments in
successful cancer chemotherapy. A significant part of tumor resistance to chemotherapy is
caused by ABC transporter P-glycoprotein (P-gp, encoded by MDR1 gene). High expression of
MDR1 and its genetic variations thus may have great clinical impact. Analyses of 6 MDR1 SNPs
and expression in 90 sets of samples from breast cancer patients were performed. MDR1
genotype was assayed with a novel method that allows simultaneous assessment of multiple
SNPs on a single Nanogen electronic microarray. MDR1 expression was quantified in cDNA
samples from tumor and non-tumor tissues of breast cancer patients by real-time PCR. Two-
sided t-test and Mann-Whitney U test were used for assessment of the effect of MDR1
polymorphisms on the MDR1 expression and for the analysis of associations with clinical and
pathological characteristics. MDR1 was expressed in 87/88 (98.9 %) of tumor and in 39/40
(97.5%) of non-tumor samples. Striking inter-individual variability in expression of MDR1 was
found. MDR1 was down-regulated in 89.7% of all tumors. No significant correlation was
observed between MDR1 expression and any clinico-pathological data. High frequencies of
variant alleles in MDR1 exon 12 (C1236T, q = 38.3) and exon 26 (C3435T, q = 54.0) were
revealed in patients. Individuals with variant alleles in these SNPs had significantly lower MDR1
expression in their tumors than patients with normal genotype. SNPs in exon 12 and exon 26 also
correlated with estrogen status of patients. Thus these SNPs may affect function of P-gp and
modify breast cancer outcome.

This work was supported by grant of GA CR 305/07/P347, IGA 8563-5 and Young Scientist
Research Program of NIPH (Prague, Czech Republic).

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