title: DNA damage repair and telomere length in normal breast, preneoplastic lesions, and invasive cancer.
abstract: OBJECTIVE
  Carcinogenesis is a multistep process involving the accumulation of genetic and molecular abnormalities. It has been suggested that there is a relationship between telomere attrition in the early stages of carcinogenesis and activation of the DNA damage response machinery. We explored telomere length modification and damage response pathway activation at 3 steps of breast carcinogenesis.
  
  
  METHODS
  We carried out a retrospective immunohistochemical analysis of pathway ataxia telangiectasia mutated (p-ATM) (series 1981) and gamma-H2AX (series 139) levels in normal breast, preneoplastic lesions, and invasive carcinoma. Fluorescent in situ hybridization was used to analyze telomere length at each stage.
  
  
  RESULTS
  ATM was activated in 45% of normal tissue samples, 70% of preneoplastic lesions, and 14% of breast carcinomas. The increase in ATM activation, between normal tissues and preneoplasia, was not significant (P = 0.095), whereas, ATM repression between preneoplasia and cancer was significant (P = 0.0023). Telomeres in preneoplastic lesions were more frequently shorter than those in normal tissues (P = 0.0116). Finally, telomere lengths were long in 38.9% and very short in 38.9% of breast carcinomas (P = 0.0087 for comparisons with preneoplastic lesions).
  
  
  CONCLUSIONS
  This study suggests that a major defect in DNA repair occurs between preneoplasia and breast cancer. This defect is associated with changes in telomere length between the preneoplastic and the cancer stage.
authors.affiliation: Département des Science du Vinvant-Laboratoire de radiobiologie et oncologie, CEA, Fontenay-aux-Roses, France.
authors.forename: Christophe M
authors.initials: CM
authors.lastname: Raynaud
authors.forename: Juana
authors.initials: J
authors.lastname: Hernandez
authors.forename: Frédérique P
authors.initials: FP
authors.lastname: Llorca
authors.forename: Paolo
authors.initials: P
authors.lastname: Nuciforo
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Mathieu
authors.forename: Frederic
authors.initials: F
authors.lastname: Commo
authors.forename: Suzette
authors.initials: S
authors.lastname: Delaloge
authors.forename: Laure
authors.initials: L
authors.lastname: Sabatier
authors.forename: Fabrice
authors.initials: F
authors.lastname: André
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Soria
mesh_terms: D000328:Adult; D000368:Aged; D001940:Breast / Q000166:cytology* / Q000473:pathology; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology*; D004249:DNA Damage; D004260:DNA Repair; D005260:Female; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D011230:Precancerous Conditions / Q000235:genetics / Q000473:pathology*; D016615:Telomere / Q000235:genetics / Q000469:parasitology / Q000648:ultrastructure*
chemical_list: C468783:H2AX protein, human; D006657:Histones