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

Navita Somaiah, John Yarnold*, Frances Daley, Ann Pearson, Lone Gothard, Kai Rothkamm, Thomas Helleday

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

22 Citations (Scopus)

Abstract

Purpose: 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 toDNAdouble-strand breaks (DSB).Humanepidermis was used as a model in which proliferation and DNA repair were correlated over 5 weeks of radiotherapy. Experimental design: Radiotherapy (25 fractions of 2 Gy) was prescribed to the breast in 30women 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 b1-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.

Original languageEnglish
Pages (from-to)5479-5488
Number of pages10
JournalClinical Cancer Research
Volume18
Issue number19
DOIs
Publication statusPublished - 1 Oct 2012

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