NAD(P)H:quinone oxidoreductase 1 NQO1*2 genotype (P187S) is a strong prognostic and predictive factor in breast cancer.
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.
Department of Obstetrics and Gynecology, Helsinki University Central Hospital, FI-00029 Helsinki, Finland.
Rainer
R
Fagerholm
Barbara
B
Hofstetter
Johanna
J
Tommiska
Kirsimari
K
Aaltonen
Radek
R
Vrtel
Kirsi
K
Syrjäkoski
Anne
A
Kallioniemi
Outi
O
Kilpivaara
Arto
A
Mannermaa
Veli-Matti
VM
Kosma
Matti
M
Uusitupa
Matti
M
Eskelinen
Vesa
V
Kataja
Kristiina
K
Aittomäki
Karl
K
von Smitten
Päivi
P
Heikkilä
Jiri
J
Lukas
Kaija
K
Holli
Jirina
J
Bartkova
Carl
C
Blomqvist
Jiri
J
Bartek
Heli
H
Nevanlinna
D000970:Antineoplastic Agents / Q000627:therapeutic use; D000975:Antioxidants / Q000378:metabolism / Q000502:physiology; D001943:Breast Neoplasms / Q000175:diagnosis* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D003131:Combined Modality Therapy; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015251:Epirubicin / Q000494:pharmacology; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D006720:Homozygote; D006801:Humans; D008954:Models, Biological; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics* / Q000502:physiology; D009362:Neoplasm Metastasis; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D016019:Survival Analysis; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D000970:Antineoplastic Agents; D000975:Antioxidants; D014409:Tumor Necrosis Factor-alpha; D015251:Epirubicin; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human