DNA polymerase theta up-regulation is associated with poor survival in breast cancer, perturbs DNA replication, and promotes genetic instability

Fanny Lemee, Valerie Bergoglio, Anne Fernandez-Vidal, Alice Machado-Silva, Marie-Jeanne Pillaire, Anne Bieth, Catherine Gentil, Lee Baker, Anne-Laure Martin, Claire Leduc, Elena Lam, Eddy Magdeleine, Thomas Filleron, Naima Oumouhou, Bernd Kaina, Mineaki Seki, Fanny Grimal, Magali Lacroix-Triki, Alastair Thompson, Henri RocheJean-Christophe Bourdon, Richard D. Wood, Jean-Sebastien Hoffmann, Christophe Cazaux

    Research output: Contribution to journalArticlepeer-review

    96 Citations (Scopus)

    Abstract

    "Replicative stress" is one of the main factors underlying neoplasia from its early stages. Genes involved in DNA synthesis may therefore represent an underexplored source of potential prognostic markers for cancer. To this aim, we generated gene expression profiles from two independent cohorts (France, n = 206; United Kingdom, n = 117) of patients with previously untreated primary breast cancers. We report here that among the 13 human nuclear DNA polymerase genes, DNA Polymerase. (POLQ) is the only one significantly up-regulated in breast cancer compared with normal breast tissues. Importantly, POLQ up-regulation significantly correlates with poor clinical outcome (4.3-fold increased risk of death in patients with high POLQ expression), and this correlation is independent of Cyclin E expression or the number of positive nodes, which are currently considered as markers for poor outcome. POLQ expression provides thus an additional indicator for the survival outcome of patients with high Cyclin E tumor expression or high number of positive lymph nodes. Furthermore, to decipher the molecular consequences of POLQ up-regulation in breast cancer, we generated human MRC5-SV cell lines that stably overexpress POLQ. Strong POLQ expression was directly associated with defective DNA replication fork progression and chromosomal damage. Therefore, POLQ overexpression may be a promising genetic instability and prognostic marker for breast cancer.

    Original languageEnglish
    Pages (from-to)13390-13395
    Number of pages6
    JournalProceedings of the National Academy of Sciences of the United States of America
    Volume107
    Issue number30
    DOIs
    Publication statusPublished - 27 Jul 2010

    Keywords

    • specialized DNA replication
    • prognosis marker
    • S-phase checkpoint
    • BASE EXCISION-REPAIR
    • DOUBLE-STRAND BREAKS
    • CHROMOSOME INSTABILITY
    • GENOMIC INSTABILITY
    • CYCLIN-E
    • DAMAGE
    • KAPPA
    • CELLS
    • BETA
    • TUMORIGENESIS

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