title: ATM down-regulation is associated with poor prognosis in sporadic breast carcinomas.
abstract: 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.
  
  
  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.
authors.affiliation: NeoGene Laboratory, Department of Urology, São Paulo State University, Botucatu.
authors.forename: R C
authors.initials: RC
authors.lastname: Bueno
authors.forename: R A
authors.initials: RA
authors.lastname: Canevari
authors.forename: R A R
authors.initials: RA
authors.lastname: Villacis
authors.forename: M A C
authors.initials: MA
authors.lastname: Domingues
authors.forename: J R F
authors.initials: JR
authors.lastname: Caldeira
authors.forename: R M
authors.initials: RM
authors.lastname: Rocha
authors.forename: S A
authors.initials: SA
authors.lastname: Drigo
authors.forename: S R
authors.initials: SR
authors.lastname: Rogatto
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001943:Breast Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000378:metabolism* / Q000401:mortality / Q000556:secondary; D016022:Case-Control Studies; D018572:Disease-Free Survival; D015536:Down-Regulation; D005260:Female; D018628:Gene Dosage; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D060787:Neoplasm Grading; D011379:Prognosis; D016016:Proportional Hazards Models
chemical_list: D014408:Biomarkers, Tumor; D035683:MicroRNAs; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins
keywords: ataxia-telangiectasia-mutated (ATM) gene; breast cancer; copy number alteration; microRNA; prognostic marker