Abstract for presentation at 11th International Congress of Human Genetics

Genetic mapping in Trp53+/- mice identifies DMBT1 as a potential modifier of breast cancer risk

  • Dr Anneke Blackburn, Australian National University, Canberra ACT, Australia
  • Dr Linda Hill, Department of Veterinary and Animal Sciences, University of Massachusetts, Amherst MA, United States
  • Jun Wang, Department of Genetics and Genomics, Roche Palo Alto, CA, United States
  • Dee Aud, Department of Genetics and Genomics, Roche Palo Alto, CA, United States
  • Dr Qing Cao, Department of Pathology, Baystate Medical Center, Springfield, MA, United States
  • Dr Stephen Naber, Department of Pathology, Baystate Medical Center, Springfield, MA, United States
  • Dr Gary Peltz, Department of Genetics and Genomics, Roche Palo Alto, CA, United States
  • Dr D Joseph Jerry, Department of Veterinary and Animal Sciences, University of Massachusetts, Amherst MA, United States

    • In mice heterozygous for p53 (Trp53+/-), a model for Li-Fraumeni syndrome, the incidence of mammary tumours varies among strains, with C57BL/6 being resistant and BALB/c being susceptible. This difference has both dominant and recessive components (Blackburn et al. Cancer Res. 63:2364, 2003). Genetic mapping in [(C57BL/6 x BALB/c) x BALB/c] -N2 Trp53+/- mice identified two novel, interacting recessive loci which increased BALB/c mammary tumour susceptibility 2.5-fold (95% CI 1.4-4.5, p=0.002). The genome scan identified linkage regions on chr 7 (LOD 3.5, designated SuprMam1 for Suppressor of Mammary Tumours) and chr 2 (LOD 1.95, SuprMam2). Transcriptional profiling of mammary glands from C57BL/6- and BALB/c- Trp53+/- mice was performed to identify differentially expressed candidate genes. In SuprMam1, 10 genes were found to be significantly different in expression between the two strains (fold change >1.6; p<0.05), including 7 ESTs and 3 genes: Tead1 (TEA domain family member 1), Dmbt1 (Deleted in malignant brain tumors 1) and Nucb2 (nucleobindin 2). Of these known genes, only Dmbt1 had more than 2-fold difference in expression and has been described as a putative tumor suppressor gene. Northern blotting confirmed that expression of Dmbt1 in mammary glands from C57BL/6-Trp53+/- mice was over 5-fold higher than the levels in BALB/c-Trp53+/- (p=0.009). Q-PCR on mouse and human mammary tumour RNA indicated lack of expression in breast cancers and cell lines. To determine whether levels of DMBT1 may be related to risk of breast cancer, expression of DMBT1 protein was determined by immunohistochemical staining in normal breast tissues from women with breast cancer (n=46) and cancer-free controls (reduction mammoplasty, n=53). Average staining scores were significantly reduced among women with breast cancer compared with cancer-free controls (3.9 vs 1.8, respectively; P<0.0001). These results identify a novel mammary tumor susceptibility locus in mice and support a role for DMBT1 in suppression of mammary tumors in both mice and women.

    Supported by: the U.S. Army Medical Research and Materiel Command (DAMD17-00-1-0632, DAMD17-01-1-0315); NIH (R01 CA105452); NHMRC (179842, 366787).

    Conference Organiser - ICMS Pty Ltd