NQO1 guards against oxidative stress and carcinogenesis and stabilizes p53. We find that a homozygous common missense variant (NQO1(*)2, rs1800566(T), NM_000903.2:c.558C>T) that disables NQO1 strongly predicts poor survival among two independent series of women with breast cancer (P = 0.002, N = 1,005; P = 0.005, N = 1,162), an effect particularly evident after anthracycline-based adjuvant chemotherapy with epirubicin (P = 7.52 x 10(-6)) and in p53-aberrant tumors (P = 6.15 x 10(-5)). Survival after metastasis was reduced among NQO1(*)2 homozygotes, further implicating NQO1 deficiency in cancer progression and treatment resistance. Consistently, response to epirubicin was impaired in NQO1(*)2-homozygous breast carcinoma cells in vitro, reflecting both p53-linked and p53-independent roles of NQO1. We propose a model of defective anthracycline response in NQO1-deficient breast tumors, along with increased genomic instability promoted by elevated reactive oxygen species (ROS), and suggest that the NQO1 genotype is a prognostic and predictive marker for breast cancer.
- MeSH
- analýza přežití MeSH
- antioxidancia metabolismus fyziologie MeSH
- antitumorózní látky terapeutické užití MeSH
- biologické modely MeSH
- buněčná smrt účinky léků genetika MeSH
- chemorezistence genetika MeSH
- epirubicin farmakologie MeSH
- genotyp MeSH
- homozygot MeSH
- jednonukleotidový polymorfismus * MeSH
- kombinovaná terapie MeSH
- lidé MeSH
- metastázy nádorů MeSH
- NAD(P)H dehydrogenasa (chinon) * genetika fyziologie MeSH
- nádorové buňky kultivované MeSH
- nádory prsu * diagnóza genetika mortalita patologie MeSH
- následné studie MeSH
- prognóza MeSH
- TNF-alfa farmakologie MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
