6533b7d5fe1ef96bd12649cb

RESEARCH PRODUCT

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

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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,POLQup-regulation significantly correlates with poor clinical outcome (4.3-fold increased risk of death in patients with highPOLQexpression), and this correlation is independent ofCyclin Eexpression or the number of positive nodes, which are currently considered as markers for poor outcome.POLQexpression provides thus an additional indicator for the survival outcome of patients with highCyclin Etumor expression or high number of positive lymph nodes. Furthermore, to decipher the molecular consequences ofPOLQup-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,POLQoverexpression may be a promising genetic instability and prognostic marker for breast cancer.