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Primary fibroblasts from BRCA1 mutation-carrying members of breast cancer families display a G1/S cell cycle checkpoint defect following UVA irradiation but show normal levels of micronuclei following oxidative stress or mitomycin C treatment.

Shorrocks, Julie and Tobi, Simon E. and Latham, Harry and Peacock, John H. and Eeles, Ros and Eccles, Diana and McMillan, Trevor J. (2004) Primary fibroblasts from BRCA1 mutation-carrying members of breast cancer families display a G1/S cell cycle checkpoint defect following UVA irradiation but show normal levels of micronuclei following oxidative stress or mitomycin C treatment. International Journal Radiation Oncology Biology Physics, 58 (2). pp. 470-478.

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Abstract

Purpose There is evidence to suggest that the breast cancer predisposing gene, BRCA1, is involved in cell cycle control and the response to damage but mouse brca1+/− heterozygotes have no distinctive phenotype. Here the response to the three forms of cellular stress was examined in primary human fibroblasts from individuals with a +/+ or +/− genotype for BRCA1. Methods and materials Fibroblasts from individuals carrying mutations in the BRCA1 gene were compared with those from those wild-type for BRCA1 in their response to long wavelength uv (UVA), hydrogen peroxide, and mitomycin C (MMC). Cell cycle progression and micronucleus formation (MN) were used as end points. Results After UVA treatment there was no difference between +/− and +/+ cells in the initial fall in DNA synthetic activity (G1 arrest) but the reentry into S-phase was restored at a faster rate in the BRCA1+/− cells after UVA exposure. Thus, for three normal (+/+) cell lines irradiated in monolayer, S-phase values averaged 15 ± 3.7% 14 h post-UVA (1 × 105 J/m2), as compared with 35.7 ± 1.9 (range) for two BRCA1(+/−) strains. Because a defective G1/S checkpoint in BRCA1 heterozygotes could lead to a greater proportion of S-phase cells with unrepaired DNA damage (strand breaks) and a resultant increase in chromosomal instability, the frequency of micronuclei induced by UVA was examined. Three normal (+/+) and three mutant (+/−) strains (two of which were used in the cell cycle experiments) produced mean micronuclei frequencies of 0.077 ± 0.016 and 0.094 ± 0.04/binucleate cell respectively (not statistically significant), 48 h after UVA exposure. No differences were found between BRCA1+/+ and +/− cells in MN formation after treatment with MMC or hydrogen peroxide. Conclusion Our data suggest a defective G1/S checkpoint in cells from BRCA1 heterozygotes in response to UVA although this is not reflected in genomic instability as measured by micronuclei induction after oxidative stress or MMC treatment.

Item Type: Article
Journal or Publication Title: International Journal Radiation Oncology Biology Physics
Uncontrolled Keywords: BRCA1 ; Radiation ; DNA damage ; Cell cycle ; Checkpoint
Subjects: Q Science > QH Natural history > QH301 Biology
Departments: Faculty of Science and Technology > Lancaster Environment Centre
Faculty of Health and Medicine > Biomedical & Life Sciences
VC's Office
ID Code: 73
Deposited By: Professor Trevor McMillan
Deposited On: 12 May 2008 15:26
Refereed?: Yes
Published?: Published
Last Modified: 26 Jul 2012 18:19
Identification Number:
URI: http://eprints.lancs.ac.uk/id/eprint/73

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