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Brca1 heterozygous mice have shortened life span and are prone to ovarian tumorigenesis with haploinsufficiency upon ionizing irradiation

Abstract

BRCA1 mutation carriers have an 85% lifetime risk of breast cancer and 60% for ovarian cancer. BRCA1 facilitates DNA double-strand break repair, and dysfunction of BRCA1 leads to hypersensitivity to DNA damaging agents and consequently genomic instability of cells. In this communication, we have examined the tumor incidence and survival of Brca1 heterozygous female mice. Brca1 heterozygotes appear to have a shortened life span with 70% tumor incidence. Lymphoma, but not ovarian and mammary gland tumors, occurs commonly in these mice. After a whole-body exposure to ionizing radiation, Brca1 heterozygous mice have a 3–5-fold higher incidence specific to ovarian tumors, but not lymphoma, when compared with the Brca1+/+ mice. All the tumors from heterozygous mice examined retain the wild-type allele and the cancer cells express Brca1 protein, precluding the chromosomal mechanism for loss of heterozygosity of Brca1 locus. Although the manifestation of BRCA1 haploinsufficiency may be different between human and mouse, this study suggests that women carrying Brca1 mutations may be more prone to ovarian tumor formation after IR exposure than nonmutation carriers.

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Acknowledgements

We thank Chi-Fen Chen and Xiaoqin Lin for their kind assistance. This work was supported by a grant from the National Institute of Health (RO1 94170) to W-H Lee, a predoctoral fellowship from the Department of Defense (W81XWH-05-1-0322 to SF), and a physician scientist award from the National Health Research Institute in Taiwan to Y-M J.

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Correspondence to W-H Lee.

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Jeng, YM., Cai-Ng, S., Li, A. et al. Brca1 heterozygous mice have shortened life span and are prone to ovarian tumorigenesis with haploinsufficiency upon ionizing irradiation. Oncogene 26, 6160–6166 (2007). https://doi.org/10.1038/sj.onc.1210451

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  • DOI: https://doi.org/10.1038/sj.onc.1210451

Keywords

  • BRCA1
  • heterozygous mutant
  • ionizing radiation
  • ovarian tumor
  • haploinsufficiency

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