title: Overexpression of NAD(P)H:quinone oxidoreductase 1 (NQO1) and genomic gain of the NQO1 locus modulates breast cancer cell sensitivity to quinones.
abstract: OBJECTIVE
  Alterations in the expression of antioxidant enzymes are associated with changes in cancer cell sensitivity to chemotherapeutic drugs (menadione and β-lapachone). Mechanisms of acquisition of resistance to pro-oxidant drugs were investigated using a model of oxidative stress-resistant MCF-7 breast cancer cells (Resox cells).
  
  
  METHODS
  FISH experiments were performed in tumor biopsy and breast cancer cells to characterize the pattern of the NQO1 gene. SNP-arrays were conducted to detect chromosomal imbalances. Finally, the importance of NQO1 overexpression in the putative acquisition of either drug resistance or an increased sensitivity to quinones by cancer cells was investigated by immunoblotting and cytotoxicity assays.
  
  
  RESULTS
  Genomic gain of the chromosomal band 16q22 was detected in Resox cells compared to parental breast cancer MCF-7 cells and normal human mammary epithelial 250MK cells. This genomic gain was associated with amplification of the NQO1 gene in one tumor biopsy as well as in breast cancer cell lines. Using different breast cell models, we found that NQO1 overexpression was a main determinant for a potential chemotherapy resistance or an increased sensitivity to quinone-bearing compounds.
  
  
  CONCLUSIONS
  Because NQO1 is frequently modified in tumors at genomic and transcriptomic levels, the impact of NQO1 modulation on breast cancer cell sensitivity places NQO1 as a potential link between cancer redox alterations and resistance to chemotherapy. Thus, the NQO1 gene copy number and NQO1 activity should be considered when quinone-bearing molecules are being utilized as potential drugs against breast tumors.
authors.affiliation: Université catholique de Louvain, Louvain Drug Research Institute, Toxicology and Cancer Biology Research Group, Brussels, Belgium.
authors.forename: Christophe
authors.initials: C
authors.lastname: Glorieux
authors.affiliation: Université catholique de Louvain, Louvain Drug Research Institute, Toxicology and Cancer Biology Research Group, Brussels, Belgium.
authors.forename: Juan Marcelo
authors.initials: JM
authors.lastname: Sandoval
authors.affiliation: Université catholique de Louvain, Louvain Drug Research Institute, Toxicology and Cancer Biology Research Group, Brussels, Belgium.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Dejeans
authors.affiliation: Centre de Génétique Humaine, Cliniques Universitaires Saint-Luc & de Duve Institute, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Geneviève
authors.initials: G
authors.lastname: Ameye
authors.affiliation: Centre de Génétique Humaine, Cliniques Universitaires Saint-Luc & de Duve Institute, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Hélène Antoine
authors.initials: HA
authors.lastname: Poirel
authors.affiliation: Université catholique de Louvain, Louvain Drug Research Institute, Toxicology and Cancer Biology Research Group, Brussels, Belgium.
authors.forename: Julien
authors.initials: J
authors.lastname: Verrax
authors.affiliation: Université catholique de Louvain, Louvain Drug Research Institute, Toxicology and Cancer Biology Research Group, Brussels, Belgium; Facultad de Ciencias de la Salud, Universidad Arturo Prat, Iquique, Chile. Electronic address: pedro.buccalderon@uclouvain.be.
authors.forename: Pedro Buc
authors.initials: PB
authors.lastname: Calderon
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001940:Breast / Q000187:drug effects* / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D005260:Female; D018628:Gene Dosage; D056426:Genetic Loci; D006801:Humans; D061986:MCF-7 Cells; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011809:Quinones / Q000737:chemistry / Q000494:pharmacology*; D015854:Up-Regulation
chemical_list: D000970:Antineoplastic Agents; D011809:Quinones; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human
keywords: Breast cancer cells; Genomic gain; Menadione; NQO1; Redox alterations; β-Lapachone