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
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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. / Somaiah, Navita; Yarnold, John; Daley, Frances; Pearson, Ann; Gothard, Lone; Rothkamm, Kai; Helleday, Thomas.
in: CLIN CANCER RES, Jahrgang 18, Nr. 19, 01.10.2012, S. 5479-88.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - 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
AU - Somaiah, Navita
AU - Yarnold, John
AU - Daley, Frances
AU - Pearson, Ann
AU - Gothard, Lone
AU - Rothkamm, Kai
AU - Helleday, Thomas
PY - 2012/10/1
Y1 - 2012/10/1
N2 - 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 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.EXPERIMENTAL DESIGN: 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.
AB - 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 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.EXPERIMENTAL DESIGN: 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.
KW - Breast/metabolism
KW - Breast Neoplasms/metabolism
KW - Cell Cycle Checkpoints/radiation effects
KW - Cyclin-Dependent Kinase Inhibitor p21/metabolism
KW - DNA Breaks, Double-Stranded/radiation effects
KW - DNA Damage/radiation effects
KW - Epidermis/metabolism
KW - Female
KW - Humans
KW - Middle Aged
KW - Radiation Tolerance
KW - Recombinational DNA Repair/genetics
U2 - 10.1158/1078-0432.CCR-10-3297
DO - 10.1158/1078-0432.CCR-10-3297
M3 - SCORING: Journal article
C2 - 22855580
VL - 18
SP - 5479
EP - 5488
JO - CLIN CANCER RES
JF - CLIN CANCER RES
SN - 1078-0432
IS - 19
ER -