title: The relationship between homologous recombination repair and the sensitivity of human epidermis to the size of daily doses over a 5-week course of breast radiotherapy.
abstract: OBJECTIVE
  A molecular understanding of tissue sensitivity to radiotherapy fraction size is missing. Here, we test the hypothesis that sensitivity to fraction size is influenced by the DNA repair system activated in response to DNA double-strand breaks (DSB). Human epidermis was used as a model in which proliferation and DNA repair were correlated over 5 weeks of radiotherapy.
  
  
  METHODS
  Radiotherapy (25 fractions of 2 Gy) was prescribed to the breast in 30 women with early breast cancer. Breast skin biopsies were collected 2 hours after the 1st and 25th fractions. Samples of contralateral breast skin served as controls. Sections were coimmunostained for Ki67, cyclin A, p21, RAD51, 53BP1, and β1-integrin.
  
  
  RESULTS
  After 5 weeks of radiotherapy, the mean basal Ki67 density increased from 5.72 to 15.46 cells per millimeter of basement membrane (P = 0.002), of which the majority were in S/G2 phase, as judged by cyclin A staining (P < 0.0003). The p21 index rose from 2.8% to 87.4% (P < 0.0001) after 25 fractions, indicating cell cycle arrest. By week 5, there was a 4-fold increase (P = 0.0003) in the proportion of Ki67-positive cells showing RAD51 foci, suggesting increasing activation of homologous recombination.
  
  
  CONCLUSIONS
  Cell cycle arrest in S/G2 phase in the basal epidermis after a 5-week course of radiotherapy is associated with greater use of homologous recombination for repairing DSB. The high fidelity of homologous recombination, which is independent of DNA damage levels, may explain the low-fractionation sensitivity of tissues with high-proliferative indices, including self-renewing normal tissues and many cancers.
authors.affiliation: Gray Institute for Radiation Oncology & Biology, University of Oxford, Oxford, UK.
authors.forename: Navita
authors.initials: N
authors.lastname: Somaiah
authors.forename: John
authors.initials: J
authors.lastname: Yarnold
authors.forename: Frances
authors.initials: F
authors.lastname: Daley
authors.forename: Ann
authors.initials: A
authors.lastname: Pearson
authors.forename: Lone
authors.initials: L
authors.lastname: Gothard
authors.forename: Kai
authors.initials: K
authors.lastname: Rothkamm
authors.forename: Thomas
authors.initials: T
authors.lastname: Helleday
mesh_terms: D001940:Breast / Q000378:metabolism / Q000528:radiation effects; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D059447:Cell Cycle Checkpoints / Q000528:radiation effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded / Q000528:radiation effects; D004249:DNA Damage / Q000528:radiation effects; D004817:Epidermis / Q000378:metabolism / Q000528:radiation effects; D005260:Female; D006801:Humans; D008875:Middle Aged; D011836:Radiation Tolerance; D059767:Recombinational DNA Repair / Q000235:genetics / Q000528:radiation effects
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21