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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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.

Author information

Author notes

    • Rainer Fagerholm
    • , Barbara Hofstetter
    •  & Johanna Tommiska

    These authors contributed equally to this work.

Affiliations

  1. Department of Obstetrics and Gynecology, Helsinki University Central Hospital, FI-00029 Helsinki, Finland.

    • Rainer Fagerholm
    • , Johanna Tommiska
    • , Kirsimari Aaltonen
    • , Outi Kilpivaara
    •  & Heli Nevanlinna
  2. Institute of Cancer Biology and Centre for Genotoxic Stress Research, Danish Cancer Society, DK-2100 Copenhagen, Denmark.

    • Barbara Hofstetter
    • , Radek Vrtel
    • , Jiri Lukas
    • , Jirina Bartkova
    •  & Jiri Bartek
  3. Department of Oncology, Helsinki University Central Hospital, FI-00029 Helsinki, Finland.

    • Kirsimari Aaltonen
    •  & Carl Blomqvist
  4. Laboratory of Cancer Genetics, Tampere University Hospital and Institute of Medical Technology, University of Tampere, FI-33014 Tampere, Finland.

    • Kirsi Syrjäkoski
    •  & Anne Kallioniemi
  5. Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Kuopio, FI-70211 Kuopio, Finland.

    • Arto Mannermaa
    •  & Veli-Matti Kosma
  6. Department of Pathology, Kuopio University Hospital, FI-70211 Kuopio, Finland.

    • Arto Mannermaa
    •  & Veli-Matti Kosma
  7. Department of Public Health and Clinical Nutrition, Kuopio University Hospital, FI-70211 Kuopio, Finland.

    • Matti Uusitupa
  8. Department of Surgery, Kuopio University Hospital, FI-70211 Kuopio, Finland.

    • Matti Eskelinen
  9. Department of Oncology, Kuopio University Hospital, FI-70211 Kuopio, Finland.

    • Vesa Kataja
  10. Department of Oncology, Vaasa Central Hospital, FI-651000 Vaasa, Finland.

    • Vesa Kataja
  11. Department of Clinical Genetics, Helsinki University Central Hospital, FI-00029 Helsinki, Finland.

    • Kristiina Aittomäki
  12. Department of Surgery, Helsinki University Central Hospital, FI-00029 Helsinki, Finland.

    • Karl von Smitten
  13. Department of Pathology, Helsinki University Central Hospital, FI-00029 Helsinki, Finland.

    • Päivi Heikkilä
  14. Medical School, University of Tampere, and Palliative Unit, Tampere University Hospital, FI-33014 Tampere, Finland.

    • Kaija Holli
  15. Department of Oncology, Radiology and Clinical Immunology, Uppsala University Hospital, SE-75185 Uppsala, Sweden.

    • Carl Blomqvist
  16. Laboratory of Genome Integrity, Palacky University, CZ-77515 Olomouc, Czech Republic.

    • Radek Vrtel
    •  & Jiri Bartek

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Competing interests

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.

Corresponding authors

Correspondence to Jiri Bartek or Heli Nevanlinna.

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