DNA polymerase theta up-regulation is associated with poor survival in breast cancer, perturbs DNA replication, and promotes genetic instability.
Proc Natl Acad Sci U S A
; 107(30): 13390-5, 2010 Jul 27.
Article
in En
| MEDLINE
| ID: mdl-20624954
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Breast Neoplasms
/
Genomic Instability
/
DNA-Directed DNA Polymerase
/
DNA Replication
Type of study:
Clinical_trials
/
Etiology_studies
/
Incidence_studies
/
Observational_studies
/
Prognostic_studies
/
Risk_factors_studies
Limits:
Female
/
Humans
/
Middle aged
Country/Region as subject:
Europa
Language:
En
Journal:
Proc Natl Acad Sci U S A
Year:
2010
Document type:
Article
Affiliation country:
France