NAD(P)H:quinone oxidoreductase 1 NQO1*2 genotype (P187S) is a strong prognostic and predictive factor in breast cancer

Abstract

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 × 10−6) and in p53-aberrant tumors (P = 6.15 × 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.

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Figure 1: Comparisons of Kaplan-Meier survival curves between NQO1 genotypes among subgroups of individuals.
Figure 2: Proliferation and cell death in epirubicin-treated human cell lines with different NQO1 status.
Figure 3: Proliferation and ROS levels in epirubicin-treated cells with different NQO1 and p53 status.
Figure 4: NQO1 status and activation of the TNF–NF-κB pathway in breast cancer.
Figure 5: Schematic model of NQO1- and p53-mediated cellular responses to epirubicin (FEC) and signals from tumor microenvironment, and the relative impact of NQO1 and/or p53 defects on breast cancer response to such treatment.

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Acknowledgements

We wish to thank the women with and without cancer participating in this study; N. Puolakka, H. Eerola and K. Rouhento for their help in sample and data collection; and J. Forsström, J. Sand, M. Lee and E. Myöhänen for technical assistance. Finnish Cancer Registry is gratefully acknowledged for cancer data. We further thank G. Asher (Department of Molecular Genetics, Weizmann Institute of Science, Israel) for the NQO1 plasmids, M. Oren (Weizmann Institute of Science, Israel) for the p53DD plasmid, C. Lukas (Institute of Cancer Biology, Copenhagen, Denmark) for the U2OS-p53DD cells and M.M. Briehl (Department of Pathology, University of Arizona, USA) for MCF7 cell lines. This work was supported by the Academy of Finland (110663), Finnish Cancer Society, Helsinki University Central Hospital Research Fund, the Sigrid Juselius Fund, the Danish Cancer Society, the Danish National Research Foundation, the Danish Centre for Translational Breast Cancer Research, the European Commission (integrated projects 'Mutant p53' and 'Active p53'), the Czech Ministry of Education (MSM6198959216), the Special Government Funding (EVO) of Kuopio University Hospital and Cancer Fund of North Savo.

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Correspondence to Jiri Bartek or Heli Nevanlinna.

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Licentia Ltd., representing Helsinki University Central Hospital and University of Helsinki, filed PCT-patent application PCT/FI2007/050637, “Method for predicting the response to a therapy,” on 23 November 2007.

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Fagerholm, R., Hofstetter, B., Tommiska, J. et al. NAD(P)H:quinone oxidoreductase 1 NQO1*2 genotype (P187S) is a strong prognostic and predictive factor in breast cancer. Nat Genet 40, 844–853 (2008). https://doi.org/10.1038/ng.155

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