title: NQO1 expression correlates inversely with NFκB activation in human breast cancer.
abstract: NQO1 participates in cellular defense against oxidative stress and regulates apoptosis via p53- and NFκB-mediated pathways. We have previously found that homozygous missense variant NQO1*2 (rs1800566) predicts poor survival among breast cancer patients, particularly after anthracycline-based adjuvant chemotherapy. Here, we investigated NQO1 and NFκB protein expression and global gene expression profiles in breast tumors with correlation to tumor characteristics and survival after adjuvant chemotherapy. We used immunohistochemical analysis of tissue microarrays to study NQO1 and NFκB expression in two series of tumors: 1000 breast tumors unselected for treatment and 113 from a clinical trial comparing chemotherapy regimens after anthracycline treatment in advanced breast cancer. We used gene expression arrays to define genes co-expressed with NQO1 and NFκB. NQO1 and nuclear NFκB were expressed in 83% and 11% of breast tumors, and correlated inversely (P = 0.012). NQO1 protein expression was associated with estrogen receptor (ER) expression (P = 0.011), whereas 34.5% of NFκB-nuclear/activated tumors were ER negative (P = 0.001). NQO1 protein expression and NFκB activation showed only trends, but no statistical significance for patient survival or outcome after anthracycline treatment. Gene expression analysis highlighted 193 genes that significantly correlated with both NQO1 and NFκB in opposite directions, consistent with the expression patterns of the two proteins. Inverse correlation was found with genes related to oxidation/reduction, lipid biosynthesis and steroid metabolism, immune response, lymphocyte activation, Jak-STAT signaling and apoptosis. The inverse relationship between NQO1 protein expression and NFκB activation, underlined also by inverse patterns of association with ER and gene expression profiles of tumors, suggests that NQO1-NFκB interaction in breast cancer is different from several other tissue types, possibly due to estrogen receptor signaling in breast cancer. Neither NQO1 nor NFκB protein expression appear as significant prognostic or predictive markers in breast cancer.
authors.affiliation: Department of Obstetrics and Gynecology, Biomedicum Helsinki, Helsinki University Central Hospital, PO Box 700, 00029 Helsinki, Finland.
authors.forename: Maral
authors.initials: M
authors.lastname: Jamshidi
authors.forename: Jirina
authors.initials: J
authors.lastname: Bartkova
authors.forename: Dario
authors.initials: D
authors.lastname: Greco
authors.forename: Johanna
authors.initials: J
authors.lastname: Tommiska
authors.forename: Rainer
authors.initials: R
authors.lastname: Fagerholm
authors.forename: Kristiina
authors.initials: K
authors.lastname: Aittomäki
authors.forename: Johanna
authors.initials: J
authors.lastname: Mattson
authors.forename: Kenneth
authors.initials: K
authors.lastname: Villman
authors.forename: Radek
authors.initials: R
authors.lastname: Vrtel
authors.forename: Jiri
authors.initials: J
authors.lastname: Lukas
authors.forename: Päivi
authors.initials: P
authors.lastname: Heikkilä
authors.forename: Carl
authors.initials: C
authors.lastname: Blomqvist
authors.forename: Jiri
authors.initials: J
authors.lastname: Bartek
authors.forename: Heli
authors.initials: H
authors.lastname: Nevanlinna
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D018270:Carcinoma, Ductal, Breast / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D018275:Carcinoma, Lobular / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D002467:Cell Nucleus / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D016016:Proportional Hazards Models; D012044:Regression Analysis
chemical_list: D016328:NF-kappa B; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human