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DNA polymerase θ up-regulation is associated with poor survival in breast cancer, perturbs DNA replication, and promotes genetic instability
Fanny Lemée, Valérie 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, Naïma Oumouhou, Bernd Kaina, Mineaki Seki, Fanny Grimal, Magali Lacroix-Triki, Alastair Thompson, Henri Roché, Jean-Christophe Bourdon, Richard D. Wood, Jean-Sébastien Hoffmann, Christophe Cazaux and Philip C. Hanawalt
Proceedings of the National Academy of Sciences of the United States of America
Vol. 107, No. 30 (July 27, 2010), pp. 13390-13395
Published by: National Academy of Sciences
Stable URL: http://www.jstor.org/stable/25708726
Page Count: 6
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"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 θ (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.
Proceedings of the National Academy of Sciences of the United States of America © 2010 National Academy of Sciences