ATM down-regulation is associated with poor prognosis in sporadic breast carcinomas
R C Bueno1, R A Canevari, R A R Villacis
1NeoGene Laboratory, Department of Urology, São Paulo State University, Botucatu.
Background:
Ataxia telangiectasia-mutated (ATM) gene downexpression has been reported in sporadic breast carcinomas (BC); however, the prognostic value and mechanisms of ATM deregulation remain unclear.
Patients And Methods:
ATM and miRNAs (miR-26a, miR-26b, miR-203, miR-421, miR-664, miR-576-5p and miR-18a) expression levels were evaluated by quantitative real-time PCR (RT-qPCR) in 52 BC and 3 normal breast samples. ATM protein expression was assessed by immunohistochemistry in 968 BC and 35 adjacent normal breast tissues. ATM copy number alteration was detected by array comparative genomic hybridization (aCGH) in 42 tumours.
Results:
Low ATM levels were associated with tumour grade. Absence of ATM protein expression was associated with distant metastasis (P < 0.001), reduced disease-free survival (DFS, P < 0.001) and cancer-specific survival (CSS, P < 0.001). Multivariate analysis indicated ATM protein expression as an independent prognostic marker for DFS (P = 0.001, HR = 0.579) and CSS (P = 0.001, HR = 0.554). ATM copy number loss was detected in 12% of tumours and associated with lower mRNA levels. miR-421 over-expression was detected in 36.5% of cases which exhibit lower ATM transcript levels (P = 0.075, r = -0.249).
Conclusions:
The data suggest that ATM protein expression is an independent prognostic marker in sporadic BC. Gene copy number loss and miR-421 over-expression may be involved in ATM deregulation in BC.
Insights
Ataxia telangiectasia-mutated (ATM) gene expression is a significant prognostic marker in breast cancer (BC). Low ATM levels correlate with poor survival, and its deregulation may involve gene copy loss and miR-421 overexpression.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Ataxia telangiectasia-mutated (ATM) gene downexpression is observed in sporadic breast carcinomas (BC).
- The prognostic significance and mechanisms of ATM deregulation in BC are not fully understood.
Purpose of the Study:
- To investigate the prognostic value of ATM expression in sporadic breast cancer.
- To explore potential mechanisms of ATM deregulation, including gene copy number alterations and microRNA involvement.
Main Methods:
- Quantitative real-time PCR (RT-qPCR) for ATM and miRNA expression.
- Immunohistochemistry for ATM protein assessment in a large cohort of BC tissues.
- Array comparative genomic hybridization (aCGH) for ATM copy number analysis.
Main Results:
- Absence of ATM protein expression strongly correlates with distant metastasis and reduced disease-free survival (DFS) and cancer-specific survival (CSS).
- ATM protein expression is an independent prognostic marker for DFS and CSS.
- ATM copy number loss and miR-421 overexpression are associated with reduced ATM mRNA levels.
Conclusions:
- ATM protein expression serves as an independent prognostic indicator in sporadic breast cancer.
- Gene copy number loss and miR-421 overexpression are implicated in the deregulation of ATM in BC.
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