TY - JOUR
T1 - DNA polymerase theta up-regulation is associated with poor survival in breast cancer, perturbs DNA replication, and promotes genetic instability
AU - Lemee, Fanny
AU - Bergoglio, Valerie
AU - Fernandez-Vidal, Anne
AU - Machado-Silva, Alice
AU - Pillaire, Marie-Jeanne
AU - Bieth, Anne
AU - Gentil, Catherine
AU - Baker, Lee
AU - Martin, Anne-Laure
AU - Leduc, Claire
AU - Lam, Elena
AU - Magdeleine, Eddy
AU - Filleron, Thomas
AU - Oumouhou, Naima
AU - Kaina, Bernd
AU - Seki, Mineaki
AU - Grimal, Fanny
AU - Lacroix-Triki, Magali
AU - Thompson, Alastair
AU - Roche, Henri
AU - Bourdon, Jean-Christophe
AU - Wood, Richard D.
AU - Hoffmann, Jean-Sebastien
AU - Cazaux, Christophe
PY - 2010/7/27
Y1 - 2010/7/27
N2 - "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.
AB - "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.
KW - specialized DNA replication
KW - prognosis marker
KW - S-phase checkpoint
KW - BASE EXCISION-REPAIR
KW - DOUBLE-STRAND BREAKS
KW - CHROMOSOME INSTABILITY
KW - GENOMIC INSTABILITY
KW - CYCLIN-E
KW - DAMAGE
KW - KAPPA
KW - CELLS
KW - BETA
KW - TUMORIGENESIS
U2 - 10.1073/pnas.0910759107
DO - 10.1073/pnas.0910759107
M3 - Article
C2 - 20624954
SN - 0027-8424
VL - 107
SP - 13390
EP - 13395
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 30
ER -