title: DNA polymerase theta up-regulation is associated with poor survival in breast cancer, perturbs DNA replication, and promotes genetic instability.
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.
authors.affiliation: Centre National de la Recherche Scientifique, Institut de Pharmacologie et de Biologie Structurale and Université de Toulouse, Université Paul Sabatier, 31077 Toulouse, France.
authors.forename: Fanny
authors.initials: F
authors.lastname: Lemée
authors.forename: Valérie
authors.initials: V
authors.lastname: Bergoglio
authors.forename: Anne
authors.initials: A
authors.lastname: Fernandez-Vidal
authors.forename: Alice
authors.initials: A
authors.lastname: Machado-Silva
authors.forename: Marie-Jeanne
authors.initials: MJ
authors.lastname: Pillaire
authors.forename: Anne
authors.initials: A
authors.lastname: Bieth
authors.forename: Catherine
authors.initials: C
authors.lastname: Gentil
authors.forename: Lee
authors.initials: L
authors.lastname: Baker
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Martin
authors.forename: Claire
authors.initials: C
authors.lastname: Leduc
authors.forename: Elena
authors.initials: E
authors.lastname: Lam
authors.forename: Eddy
authors.initials: E
authors.lastname: Magdeleine
authors.forename: Thomas
authors.initials: T
authors.lastname: Filleron
authors.forename: Naïma
authors.initials: N
authors.lastname: Oumouhou
authors.forename: Bernd
authors.initials: B
authors.lastname: Kaina
authors.forename: Mineaki
authors.initials: M
authors.lastname: Seki
authors.forename: Fanny
authors.initials: F
authors.lastname: Grimal
authors.forename: Magali
authors.initials: M
authors.lastname: Lacroix-Triki
authors.forename: Alastair
authors.initials: A
authors.lastname: Thompson
authors.forename: Henri
authors.initials: H
authors.lastname: Roché
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Bourdon
authors.forename: Richard D
authors.initials: RD
authors.lastname: Wood
authors.forename: Jean-Sébastien
authors.initials: JS
authors.lastname: Hoffmann
authors.forename: Christophe
authors.initials: C
authors.lastname: Cazaux
mesh_terms: 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
chemical_list: D019927:Cyclin E; D004259:DNA-Directed DNA Polymerase; D000097462:DNA Polymerase theta