• 1.

    Sorenmo K. Canine mammary gland tumors. Vet Clin North Am Small Anim Pract 2003;33:573596.

  • 2.

    Priester WA, Mantel N. Occurrence of tumors in domestic animals. Data from 12 United States and Canadian colleges of veterinary medicine. J Natl Cancer Inst 1971;47:13331344.

    • Search Google Scholar
    • Export Citation
  • 3.

    Dorn CR, Taylor DO, Schneider R, et al. Survey of animal neoplasms in Alameda and Contra Costa Counties, California. II. Cancer morbidity in dogs and cats from Alameda County. J Natl Cancer Inst 1968;40:307318.

    • Search Google Scholar
    • Export Citation
  • 4.

    Moe L. Population-based incidence of mammary tumours in some dog breeds. J Reprod Fertil Suppl 2001;57:439443.

  • 5.

    Fidler IJ, Brodey RS. The biological behavior of canine mammary neoplasms. J Am Vet Med Assoc 1967;151:13111318.

  • 6.

    Hamilton JM. Comparative aspects of mammary tumors. Adv Cancer Res 1974;19:145.

  • 7.

    Priester WA. Occurrence of mammary neoplasms in bitches in relation to breed, age, tumour type, and geographical region from which reported. J Small Anim Pract 1979;20:111.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8.

    Davies AA, Masson JY, McIlwraith MJ, et al. Role of BRCA2 in control of the RAD51 recombination and DNA repair protein. Mol Cell 2001;7:273282.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9.

    Pellegrini L, Yu DS, Lo T, et al. Insights into DNA recombination from the structure of a RAD51-BRCA2 complex. Nature 2002;420:287293.

  • 10.

    Yu DS, Sonoda E, Takeda S, et al. Dynamic control of Rad51 recombinase by self-association and interaction with BRCA2. Mol Cell 2003;12:10291041.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11.

    Sharan SK, Morimatsu M, Albrecht U, et al. Embryonic lethality and radiation hypersensitivity mediated by Rad51 in mice lacking Brca2. Nature 1997;386:804810.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12.

    Chen PL, Chen CF, Chen Y, et al. The BRC repeats in BRCA2 are critical for RAD51 binding and resistance to methyl methanesulfonate treatment. Proc Natl Acad Sci U S A 1998;95:52875292.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 13.

    Venkitaraman AR. Cancer susceptibility and the functions of BRCA1 and BRCA2. Cell 2002;108:171182.

  • 14.

    Esashi F, Christ N, Gannon J, et al. CDK-dependent phosphorylation of BRCA2 as a regulatory mechanism for recombinational repair. Nature 2005;434:598604.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 15.

    Howlett NG, Taniguchi T, Olson S, et al. Biallelic inactivation of BRCA2 in Fanconi anemia. Science 2002;297:606609.

  • 16.

    Taniguchi T, D'Andrea AD. Molecular pathogenesis of Fanconi anemia: recent progress. Blood 2006;107:42234233.

  • 17.

    Reid S, Schindler D, Hanenberg H, et al. Biallelic mutations in PALB2 cause Fanconi anemia subtype FA-N and predispose to childhood cancer. Nat Genet 2007;39:162164.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 18.

    Xia B, Dorsman JC, Ameziane N, et al. Fanconi anemia is associated with a defect in the BRCA2 partner PALB2. Nat Genet 2007;39:159161.

  • 19.

    Hussain S, Witt E, Huber PA, et al. Direct interaction of the Fanconi anaemia protein FANCG with BRCA2/FANCD1. Hum Mol Genet 2003;12:25032510.

  • 20.

    Hussain S, Wilson JB, Medhurst AL, et al. Direct interaction of FANCD2 with BRCA2 in DNA damage response pathways. Hum Mol Genet 2004;13:12411248.

  • 21.

    Wang X, Andreassen PR, D'Andrea AD. Functional interaction of monoubiquitinated FANCD2 and BRCA2/FANCD1 in chromatin. Mol Cell Biol 2004;24:58505862.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 22.

    Hussain S, Wilson JB, Blom E, et al. Tetratricopeptide-motifmediated interaction of FANCG with recombination proteins XRCC3 and BRCA2. DNA Repair (Amst) 2006;5:629640.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 23.

    Xia B, Sheng Q, Nakanishi K, et al. Control of BRCA2 cellular and clinical functions by a nuclear partner, PALB2. Mol Cell 2006;22:719729.

  • 24.

    Godthelp BC, Wiegant WW, Waisfisz Q, et al. Inducibility of nuclear Rad51 foci after DNA damage distinguishes all Fanconi anemia complementation groups from D1/BRCA2. Mutat Res 2006;594:3948.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 25.

    Ohashi A, Zdzienicka MZ, Chen J, et al. Fanconi anemia complementation group D2 (FANCD2) functions independently of BRCA2- and RAD51-associated homologous recombination in response to DNA damage. J Biol Chem 2005;280:1487714883.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 26.

    Milner J, Ponder B, Hughes-Davies L, et al. Transcriptional activation functions in BRCA2. Nature 1997;386:772773.

  • 27.

    Fuks F, Milner J, Kouzarides T. BRCA2 associates with acetyltransferase activity when bound to P/CAF. Oncogene 1998;17:25312534.

  • 28.

    Siddique H, Zou JP, Rao VN, et al. The BRCA2 is a histone acetyltransferase. Oncogene 1998;16:22832285.

  • 29.

    Shin S, Verma IM. BRCA2 cooperates with histone acetyltransferases in androgen receptor-mediated transcription. Proc Natl Acad Sci U S A 2003;100:72017206.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 30.

    Wooster R, Weber BL. Breast and ovarian cancer. N Engl J Med 2003;348:23392347.

  • 31.

    Cleton-Jansen AM, Collins N, Lakhani SR, et al. Loss of heterozygosity in sporadic breast tumours at the BRCA2 locus on chromosome 13q12-q13. Br J Cancer 1995;72:12411244.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 32.

    Collins N, McManus R, Wooster R, et al. Consistent loss of the wild type allele in breast cancers from a family linked to the BRCA2 gene on chromosome 13q12–13. Oncogene 1995;10:16731675.

    • Search Google Scholar
    • Export Citation
  • 33.

    Gudmundsson J, Johannesdottir G, Bergthorsson JT, et al. Different tumor types from BRCA2 carriers show wild-type chromosome deletions on 13q12-q13. Cancer Res 1995;55:48304832.

    • Search Google Scholar
    • Export Citation
  • 34.

    Lancaster JM, Wooster R, Mangion J, et al. BRCA2 mutations in primary breast and ovarian cancers. Nat Genet 1996;13:238240.

  • 35.

    Osorio A, de la Hoya M, Rodríguez-López R, et al. Loss of heterozygosity analysis at the BRCA loci in tumor samples from patients with familial breast cancer. Int J Cancer 2002;99:305309.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 36.

    Yoshikawa Y, Morimatsu M, Ochiai K, et al. Analysis of genetic variations in the exon 27 region of the canine BRCA2 locus. J Vet Med Sci 2005;67:10131017.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 37.

    Vassetzky NS, Kramerov DA. CAN—a pan-carnivore SINE family. Mamm Genome 2002;13:5057.

  • 38.

    Yoshikawa Y, Morimatsu M, Ochiai K, et al. Insertion/deletion polymorphism in the BRCA2 nuclear localization signal. Biomed Res 2005;26:109116.

  • 39.

    Ghebranious N, Donehower LA. Mouse models in tumor suppression. Oncogene 1998;17:33853400.

  • 40.

    Knudson AG. Antioncogenes and human cancer. Proc Natl Acad Sci U S A 1993;90:1091410921.

  • 41.

    Wong AK, Pero R, Ormonde PA, et al. RAD51 interacts with the evolutionarily conserved BRC motifs in the human breast cancer susceptibility gene brca2. J Biol Chem 1997;272:3194131944.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 42.

    Ochiai K, Morimatsu M, Yoshikawa Y, et al. Brca2 C-terminus interacts with Rad51 and contributes to nuclear focus formation in double-strand break repair of DNA. Biomed Res 2004;25:269275.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 43.

    National Human genome Research Institute Web site. The breast cancer information core database. Available at: http://research.nhgri.nih.gov/projects/bic/Member/index.shtml. Accessed Feb 28, 2007.

    • Search Google Scholar
    • Export Citation

Advertisement

Novel variations and loss of heterozygosity of BRCA2 identified in a dog with mammary tumors

Yasunaga Yoshikawa DVM1, Masami Morimatsu DVM, PhD2, Kazuhiko Ochiai DVM, PhD3, Masashi Nagano DVM, PhD4, Yukiko Tomioka DVM, PhD5, Nobuo Sasaki DVM, PhD6, Kazuyoshi Hashizume DVM, PhD7, and Toshihiko Iwanaga DVM, PhD8
View More View Less
  • 1 Laboratory of Cytology and Histology, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan.
  • | 2 Laboratory of Animal Experiment for Disease Model, Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan.
  • | 3 Innovation Center Okayama for Nanobio-targeted Therapy, Okayama University, Okayama 700-8558, Japan.
  • | 4 Department of Theriogenology, Faculty of Agriculture, Tottori University, Tottori 680-8553, Japan.
  • | 5 Laboratory of Animal Experiment for Disease Model, Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan.
  • | 6 Laboratory of Veterinary Surgery, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo 113-8657, Japan.
  • | 7 Laboratory of Veterinary Physiology, Department of Veterinary Medicine, Iwate University, Morioka 020-8550, Japan.
  • | 8 Laboratory of Cytology and Histology, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan.

Abstract

Objective—To establish novel polymorphic markers for analysis of loss of heterozygosity (LOH), so as to study the possible involvement of BRCA2 in mammary tumors obtained from dogs.

Sample Population—Blood samples, mammary gland specimens, or mammary tumors from 3 tumor-bearing dogs and 10 tumor-free dogs.

Procedures—Nucleotide sequence analysis was performed with a DNA autosequencer. Loss of heterozygosity analysis was performed for markers established in the present study. The expression level of canine BRCA2 was quantified by real-time PCR analysis.

Results—3 novel microsatellite markers with high heterozygosity rates (> 50%) were established, and the previously reported marker for canine BRCA2 gene locus was improved. These markers were used for the analysis of DNA from formalin-fixed and paraffin-embedded samples. By use of these markers, LOH in canine BRCA2 was identified as a result of recombination. In mammary tumor DNA that corresponded to the LOH-positive dog, the level of canine BRCA2 expression was decreased compared with that of nonneoplastic mammary gland tissue; the open reading frame contained 4 missense variations, 1 insertion variation, and 1 silent variation, some of which were localized to functional domains.

Conclusions and Clinical Relevance—3 novel polymorphic markers were developed for LOH analysis of canine BRCA2 and identified a dog with LOH with some variations in the functional domains. These markers could be useful for assessing the relevance of BRCA2 variation in mammary tumors of dogs.

Abstract

Objective—To establish novel polymorphic markers for analysis of loss of heterozygosity (LOH), so as to study the possible involvement of BRCA2 in mammary tumors obtained from dogs.

Sample Population—Blood samples, mammary gland specimens, or mammary tumors from 3 tumor-bearing dogs and 10 tumor-free dogs.

Procedures—Nucleotide sequence analysis was performed with a DNA autosequencer. Loss of heterozygosity analysis was performed for markers established in the present study. The expression level of canine BRCA2 was quantified by real-time PCR analysis.

Results—3 novel microsatellite markers with high heterozygosity rates (> 50%) were established, and the previously reported marker for canine BRCA2 gene locus was improved. These markers were used for the analysis of DNA from formalin-fixed and paraffin-embedded samples. By use of these markers, LOH in canine BRCA2 was identified as a result of recombination. In mammary tumor DNA that corresponded to the LOH-positive dog, the level of canine BRCA2 expression was decreased compared with that of nonneoplastic mammary gland tissue; the open reading frame contained 4 missense variations, 1 insertion variation, and 1 silent variation, some of which were localized to functional domains.

Conclusions and Clinical Relevance—3 novel polymorphic markers were developed for LOH analysis of canine BRCA2 and identified a dog with LOH with some variations in the functional domains. These markers could be useful for assessing the relevance of BRCA2 variation in mammary tumors of dogs.

Contributor Notes

Supported in part by Grants-In-Aid for Scientific Research (15208030 and 19380164) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan and Research Fellowships of the Japan Society for the Promotion of Science for Young Scientists.

Address correspondence to Dr. Morimatsu.