Inherited defects of the BRCA1 and BRCA2 genes confer a profound predisposition to breast and ovarian cancer in women. Since the identification of these breast cancer susceptibility genes by positional cloning, we have used gene targeting to develop experimental mouse models for defects in the Brca2 gene. Our studies have focused on mice lacking the carboxy terminal domain of the Brca2 protein (exon 27) because this portion of the gene product has been shown to contain nuclear localization signals and it interacts directly with the Rad51 protein which is thought to be critical for maintaining genomic stability in response to DNA damage. Using homologous recombination techniques, we generated mice that carry one (hemizygous ) or two (homozygous) mutant alleles of Brca2 exon 27. These exon 27 null mice are viable although we have observed a subtle but statistically significant deficiency in the expected number of homozygous Brca2 mutant mice. An initial study with these mice has shown that homozygous mutant Brca2 mice on a C57BL/6J background are predisposed to a low incidence of spontaneous gastric carcinoma compared to their heterozygous and wild type littermates. High- and low-level gamma radiation studies (5 & 0.3 Gy at 5 wks of age) with intercrosses between these C57BL/6 Brca2-exon 27 deficient mice and BALB/c-P53-deficient mice are being followed for neoplastic development in mammary gland and other tissues. Preliminary results from this study indicate that lifetime survival is reduced and carcinoma incidence and latency is increased in Brca2 null mice . Irradiation further increased tumor incidence and decreased survival in heterozygous mice. Fluorescent microsatellite marker-assisted breeding techniques (speed congenics) were used to transfer this Brca2 exon 27 mutation onto genetic backgrounds (BALB/c and SWR) that we have previously shown are more susceptible to radiation-induced mammary carcinogenesis. These mice strains are currently being evaluated to assess tumor susceptibility.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Intramural Research (Z01)
Project #
1Z01ES023000-16
Application #
6837419
Study Section
(LWH)
Project Start
Project End
Budget Start
Budget End
Support Year
16
Fiscal Year
2003
Total Cost
Indirect Cost
Name
U.S. National Inst of Environ Hlth Scis
Department
Type
DUNS #
City
State
Country
United States
Zip Code
McAllister, Kimberly A; Bennett, L Michelle; Houle, Chris D et al. (2002) Cancer susceptibility of mice with a homozygous deletion in the COOH-terminal domain of the Brca2 gene. Cancer Res 62:990-4
Wagner, K U; McAllister, K; Ward, T et al. (2001) Spatial and temporal expression of the Cre gene under the control of the MMTV-LTR in different lines of transgenic mice. Transgenic Res 10:545-53
Hohenstein, P; Kielman, M F; Breukel, C et al. (2001) A targeted mouse Brca1 mutation removing the last BRCT repeat results in apoptosis and embryonic lethality at the headfold stage. Oncogene 20:2544-50
Bennett, L M; McAllister, K A; Ward, T et al. (2001) Mammary tumor induction and premature ovarian failure in ApcMin mice are not enhanced by Brca2 deficiency. Toxicol Pathol 29:117-25
Bennett, L M; McAllister, K A; Malphurs, J et al. (2000) Mice heterozygous for a Brca1 or Brca2 mutation display distinct mammary gland and ovarian phenotypes in response to diethylstilbestrol. Cancer Res 60:3461-9
Lubet, R A; Zhang, Z; Wiseman, R W et al. (2000) Use of p53 transgenic mice in the development of cancer models for multiple purposes. Exp Lung Res 26:581-93
Zhang, Z; Liu, Q; Lantry, L E et al. (2000) A germ-line p53 mutation accelerates pulmonary tumorigenesis: p53-independent efficacy of chemopreventive agents green tea or dexamethasone/myo-inositol and chemotherapeutic agents taxol or adriamycin. Cancer Res 60:901-7
Bennett, L M; McAllister, K A; Blackshear, P E et al. (2000) BRCA2-null embryonic survival is prolonged on the BALB/c genetic background. Mol Carcinog 28:174-83
Blackshear, P; Mahler, J; Bennett, L M et al. (1999) Extragonadal teratocarcinoma in chimeric mice. Vet Pathol 36:457-60