title: Deletions of multidrug resistance gene loci in breast cancer leads to the down-regulation of its expression and predict tumor response to neoadjuvant chemotherapy.
abstract: Neoadjuvant chemotherapy (NAC) is intensively used for the treatment of primary breast cancer. In our previous studies, we reported that clinical tumor response to NAC is associated with the change of multidrug resistance (MDR) gene expression in tumors after chemotherapy. In this study we performed a combined analysis of MDR gene locus deletions in tumor DNA, MDR gene expression and clinical response to NAC in 73 BC patients. Copy number variations (CNVs) in biopsy specimens were tested using high-density microarray platform CytoScanTM HD Array (Affymetrix, USA). 75%-100% persons having deletions of MDR gene loci demonstrated the down-regulation of MDR gene expression. Expression of MDR genes was 2-8 times lower in patients with deletion than in patients having no deletion only in post-NAC tumors samples but not in tumor tissue before chemotherapy. All patients with deletions of ABCB1 ABCB 3 ABCC5 gene loci--7q21.1, 6p21.32, 3q27 correspondingly, and most patients having deletions in ABCC1 (16p13.1), ABCC2 (10q24), ABCG1 (21q22.3), ABCG2 (4q22.1), responded favorably to NAC. The analysis of all CNVs, including both amplification and deletion showed that the frequency of 13q14.2 deletion was 85% among patients bearing tumor with the deletion at least in one MDR gene locus versus 9% in patients with no deletions. Differences in the frequency of 13q14.2 deletions between the two groups were statistically significant (p = 2.03 × 10(-11), Fisher test, Bonferroni-adjusted p = 1.73 × 10(-8)). In conclusion, our study for the first time demonstrates that deletion MDR gene loci can be used as predictive marker for tumor response to NAC.
authors.affiliation: Laboratory of Oncovirology, Tomsk Cancer Research Institute, Tomsk, Russian Federation.|Laboratory of Translational Cell and Molecular Biomedicine, National Research Tomsk State University, Tomsk, Russian Federation.
authors.forename: Nikolai V
authors.initials: NV
authors.lastname: Litviakov
authors.affiliation: Laboratory of Translational Cell and Molecular Biomedicine, National Research Tomsk State University, Tomsk, Russian Federation.|Laboratory of Molecular Oncology and Immunology, Tomsk Cancer Research Institute, Tomsk, Russian Federation.
authors.forename: Nadezhda V
authors.initials: NV
authors.lastname: Cherdyntseva
authors.affiliation: Laboratory of Oncovirology, Tomsk Cancer Research Institute, Tomsk, Russian Federation.|Laboratory of Translational Cell and Molecular Biomedicine, National Research Tomsk State University, Tomsk, Russian Federation.
authors.forename: Matvey M
authors.initials: MM
authors.lastname: Tsyganov
authors.affiliation: Department of General Oncology, Tomsk Cancer Research Institute, Tomsk, Russian Federation.
authors.forename: Elena M
authors.initials: EM
authors.lastname: Slonimskaya
authors.affiliation: Laboratory of Oncovirology, Tomsk Cancer Research Institute, Tomsk, Russian Federation.
authors.forename: Marina K
authors.initials: MK
authors.lastname: Ibragimova
authors.affiliation: Department of General Oncology, Tomsk Cancer Research Institute, Tomsk, Russian Federation.
authors.forename: Polina V
authors.initials: PV
authors.lastname: Kazantseva
authors.affiliation: Laboratory of Translational Cell and Molecular Biomedicine, National Research Tomsk State University, Tomsk, Russian Federation.|Department of Innate Immunity and Tolerance, Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Kzhyshkowska
authors.affiliation: Department of Head and Neck Cancer, Tomsk Cancer Research Institute, Tomsk, Russian Federation.
authors.forename: Eugeniy L
authors.initials: EL
authors.lastname: Choinzonov
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D018275:Carcinoma, Lobular / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D018276:Carcinoma, Medullary / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D056915:DNA Copy Number Variations / Q000235:genetics; D015536:Down-Regulation; D018432:Drug Resistance, Multiple / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D017353:Gene Deletion; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D019450:Genes, MDR / Q000235:genetics*; D006801:Humans; D008875:Middle Aged; D000089762:Multidrug Resistance-Associated Protein 2; D020360:Neoadjuvant Therapy; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C000715087:ABCC2 protein, human; D000089762:Multidrug Resistance-Associated Protein 2; D012333:RNA, Messenger
keywords: breast cancer; chromosomal abnormalities; expression of multidrug resistance genes; microarray analysis; neoadjuvant chemotherapy