DNA polymerase theta up-regulation is associated with poor survival in breast cancer, perturbs DNA replication, and promotes genetic instability.
"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.
Lemée
Fanny
F
Centre National de la Recherche Scientifique, Institut de Pharmacologie et de Biologie Structurale and Université de Toulouse, Université Paul Sabatier, 31077 Toulouse, France.
Bergoglio
Valérie
V
Fernandez-Vidal
Anne
A
Machado-Silva
Alice
A
Pillaire
Marie-Jeanne
MJ
Bieth
Anne
A
Gentil
Catherine
C
Baker
Lee
L
Martin
Anne-Laure
AL
Leduc
Claire
C
Lam
Elena
E
Magdeleine
Eddy
E
Filleron
Thomas
T
Oumouhou
Naïma
N
Kaina
Bernd
B
Seki
Mineaki
M
Grimal
Fanny
F
Lacroix-Triki
Magali
M
Thompson
Alastair
A
Roché
Henri
H
Bourdon
Jean-Christophe
JC
Wood
Richard D
RD
Hoffmann
Jean-Sébastien
JS
Cazaux
Christophe
C
D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D015331:Cohort Studies; D019927:Cyclin E / Q000235:genetics; D004249:DNA Damage; D004261:DNA Replication / Q000187:drug effects*; D004259:DNA-Directed DNA Polymerase / Q000235:genetics*; D005260:Female; D005602:France; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D042822:Genomic Instability; D006801:Humans; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D011379:Prognosis; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D006113:United Kingdom; D015854:Up-Regulation; D000097462:DNA Polymerase theta
D019927:Cyclin E; D004259:DNA-Directed DNA Polymerase; D000097462:DNA Polymerase theta