title: ATM-depletion in breast cancer cells confers sensitivity to PARP inhibition.
abstract: BACKGROUND
  Mutations in the DNA damage response (DDR) factors, breast cancer 1 (BRCA1) and BRCA2, sensitize tumor cells to poly(ADP-ribose) polymerase (PARP) inhibitors. The ataxia telangiectasia mutated (ATM) kinase is a key DDR protein whose heterozygous germline mutation is a moderate-risk factor for developing breast cancer. In this study, we examined whether ATM inactivation in breast cancer cell lines confers sensitivity to PARP inhibitors.
  
  
  METHODS
  Wild-type BRCA1/2 breast cancer cells (i.e., MCF-7 and ZR-75-1 lines) were genetically manipulated to downregulate ATM expression then assayed for cytostaticity/cytotoxicity upon treatment with PARP inhibitors, olaparib and iniparib.
  
  
  RESULTS
  When ATM-depleted cells and their relative controls were treated with olaparib (a competitive PARP-1/2 inhibitor) and iniparib (a molecule originally described as a covalent PARP-1 inhibitor) a different response to the two compounds was observed. ATM-depletion sensitized both MCF-7 and ZR-75-1 cells to olaparib-treatment, as assessed by short and long survival assays and cell cycle profiles. In contrast, iniparib induced only a mild, ATM-dependent cytostatic effect in MCF-7 cells whereas ZR-75-1 cells were sensitive to this drug, independently of ATM inactivation. These latest results might be explained by recent observations indicating that iniparib acts with mechanisms other than PARP inhibition.
  
  
  CONCLUSIONS
  These data indicate that ATM-depletion can sensitize breast cancer cells to PARP inhibition, suggesting a potential in the treatment of breast cancers low in ATM protein expression/activity, such as those arising in mutant ATM heterozygous carriers.
authors.affiliation: Experimental Oncology, Regina Elena National Cancer Institute, Via Elio Chianesi, 53-00144 Rome, Italy. soddu@ifo.it.
authors.forename: Maria Saveria
authors.initials: MS
authors.lastname: Gilardini Montani
authors.forename: Andrea
authors.initials: A
authors.lastname: Prodosmo
authors.forename: Venturina
authors.initials: V
authors.lastname: Stagni
authors.forename: Dania
authors.initials: D
authors.lastname: Merli
authors.forename: Laura
authors.initials: L
authors.lastname: Monteonofrio
authors.forename: Veronica
authors.initials: V
authors.lastname: Gatti
authors.forename: Maria Pia
authors.initials: MP
authors.lastname: Gentileschi
authors.forename: Daniela
authors.initials: D
authors.lastname: Barilà
authors.forename: Silvia
authors.initials: S
authors.lastname: Soddu
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D001549:Benzamides / Q000494:pharmacology; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D004249:DNA Damage; D004260:DNA Repair; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D061986:MCF-7 Cells; D010793:Phthalazines / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism; D012307:Risk Factors
chemical_list: D001549:Benzamides; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C090712:iniparib; D011065:Poly(ADP-ribose) Polymerases; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C531550:olaparib