title: Low expression levels of ATM may substitute for CHEK2 /TP53 mutations predicting resistance towards anthracycline and mitomycin chemotherapy in breast cancer.
abstract: BACKGROUND
  Mutations affecting p53 or its upstream activator Chk2 are associated with resistance to DNA-damaging chemotherapy in breast cancer. ATM (Ataxia Telangiectasia Mutated protein) is the key activator of p53 and Chk2 in response to genotoxic stress. Here, we sought to evaluate ATM's potential role in resistance to chemotherapy.
  
  
  METHODS
  We sequenced ATM and assessed gene expression levels in pre-treatment biopsies from 71 locally advanced breast cancers treated in the neoadjuvant setting with doxorubicin monotherapy or mitomycin combined with 5-fluorouracil. Findings were confirmed in a separate patient cohort treated with epirubicin monotherapy. Each tumor was previously analyzed for CHEK2 and TP53 mutation status.
  
  
  RESULTS
  While ATM mutations were not associated with chemo-resistance, low ATM expression levels predicted chemo-resistance among patients with tumors wild-type for TP53 and CHEK2 (P = 0.028). Analyzing the ATM-chk2-p53 cascade, low ATM levels (defined as the lower 5 to 50% percentiles) or mutations inactivating TP53 or CHEK2 robustly predicted anthracycline resistance (P-values varying between 0.001 and 0.027 depending on the percentile used to define "low" ATM levels). These results were confirmed in an independent cohort of 109 patients treated with epirubicin monotherapy. In contrast, ATM-levels were not suppressed in resistant tumors harboring TP53 or CHEK2 mutations (P > 0.5).
  
  
  CONCLUSIONS
  Our data indicate loss of function of the ATM-Chk2-p53 cascade to be strongly associated with resistance to anthracycline/mitomycin-containing chemotherapy in breast cancer.
authors.affiliation: Section of Oncology, Institute of Medicine, University of Bergen, Jonas Lies vei 65, Bergen, 5020, Norway. per.lonning@helse-bergen.no.
authors.forename: Stian
authors.initials: S
authors.lastname: Knappskog
authors.forename: Ranjan
authors.initials: R
authors.lastname: Chrisanthar
authors.forename: Erik
authors.initials: E
authors.lastname: Løkkevik
authors.forename: Gun
authors.initials: G
authors.lastname: Anker
authors.forename: Bjørn
authors.initials: B
authors.lastname: Østenstad
authors.forename: Steinar
authors.initials: S
authors.lastname: Lundgren
authors.forename: Terje
authors.initials: T
authors.lastname: Risberg
authors.forename: Ingvil
authors.initials: I
authors.lastname: Mjaaland
authors.forename: Beryl
authors.initials: B
authors.lastname: Leirvaag
authors.forename: Hrvoje
authors.initials: H
authors.lastname: Miletic
authors.forename: Per E
authors.initials: PE
authors.lastname: Lønning
mesh_terms: D018943:Anthracyclines / Q000008:administration & dosage / Q000627:therapeutic use; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D064007:Ataxia Telangiectasia Mutated Proteins; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D018797:Cell Cycle Proteins / Q000235:genetics*; D064447:Checkpoint Kinase 2; D015331:Cohort Studies; D004268:DNA-Binding Proteins / Q000235:genetics*; D004317:Doxorubicin / Q000008:administration & dosage / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D015251:Epirubicin / Q000008:administration & dosage / Q000627:therapeutic use; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000627:therapeutic use; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016685:Mitomycin / Q000008:administration & dosage / Q000627:therapeutic use; D009154:Mutation; D017239:Paclitaxel / Q000008:administration & dosage / Q000627:therapeutic use; D011237:Predictive Value of Tests; D011401:Promoter Regions, Genetic; D011446:Prospective Studies; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000627:therapeutic use; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D018943:Anthracyclines; D000903:Antibiotics, Antineoplastic; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D015251:Epirubicin; D016685:Mitomycin; D004317:Doxorubicin; D064447:Checkpoint Kinase 2; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases; D017239:Paclitaxel; D005472:Fluorouracil