ATM has a major role in the double-strand break repair pathway dysregulation in sporadic breast carcinomas and is an independent prognostic marker at both mRNA and protein levels.
BACKGROUND
Ataxia telangiectasia mutated (ATM) is a kinase that has a central role in the maintenance of genomic integrity by activating cell cycle checkpoints and promoting repair of DNA double-strand breaks (DSB). In breast cancer, a low level of ATM was correlated with poor outcome; however, the molecular mechanism of this downregulation is still unclear.


METHODS
We used qRT-PCR assay to quantify mRNA levels of ATM gene in 454 breast tumours from patients with known clinical/pathological status and outcome; reverse phase protein arrays (RPPA) were used to assess the levels of ATM and 14 proteins in 233 breast tumours.


RESULTS
ATM mRNA was associated with poor metastasis-free survival (MFS) (P=0.00012) on univariate analysis. ATM mRNA and protein levels were positively correlated (P=0.00040). A low level of ATM protein was correlated with poorer MFS (P=0.000025). ATM expression at mRNA or protein levels are independent prognostic factors on multivariate analysis (P=0.00046 and P=0.00037, respectively). The ATM protein level was positively correlated with the levels of six proteins of the DSB repair pathway: H2AX (P<0.0000001), XRCC5 (P<0.0000001), NBN (P<0.0000001), Mre11 (P=0.0000029), Rad50 (P=0.0064), and TP53BP1 (P=0.026), but not with proteins involved in other pathways that are altered in cancer. Low expression of ATM protein was significantly associated with high miR-203 expression (P=0.011).


CONCLUSIONS
We confirmed that ATM expression is an independent prognostic marker at both RNA and protein levels. We showed that alteration of ATM is involved in dysregulation of the DSB repair pathway. Finally, miR-203 may be responsible for downregulation of ATM in breast cancers.
Pharmacogenomics Unit, Department of Genetics, Institut Curie, 26 rue d'Ulm, Paris 75005, France.
S
S
Rondeau
Pharmacogenomics Unit, Department of Genetics, Institut Curie, 26 rue d'Ulm, Paris 75005, France.
S
S
Vacher
Department of Translational Research, Institut Curie, 26 rue d'Ulm, Paris 75005, France.
L
L
De Koning
Pharmacogenomics Unit, Department of Genetics, Institut Curie, 26 rue d'Ulm, Paris 75005, France.
A
A
Briaux
Pharmacogenomics Unit, Department of Genetics, Institut Curie, 26 rue d'Ulm, Paris 75005, France.
A
A
Schnitzler
Pharmacogenomics Unit, Department of Genetics, Institut Curie, 26 rue d'Ulm, Paris 75005, France.
W
W
Chemlali
Pharmacogenomics Unit, Department of Genetics, Institut Curie, 26 rue d'Ulm, Paris 75005, France.
C
C
Callens
Pharmacogenomics Unit, Department of Genetics, Institut Curie, 26 rue d'Ulm, Paris 75005, France.
R
R
Lidereau
1] Pharmacogenomics Unit, Department of Genetics, Institut Curie, 26 rue d'Ulm, Paris 75005, France [2] EA7331, University of Paris Descartes, 4 Avenue de l'Observatoire, Paris 75006, France.
I
I
Bièche
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics*; D014408:Biomarkers, Tumor / Q000235:genetics*; D001943:Breast Neoplasms / Q000175:diagnosis / Q000235:genetics*; D002277:Carcinoma / Q000175:diagnosis / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000235:genetics; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics; D015536:Down-Regulation; D005260:Female; D006801:Humans; D035683:MicroRNAs / Q000235:genetics; D008875:Middle Aged; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics
D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C546703:MIRN203 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins