Abstract for presentation at 11th International Congress of Human Genetics

Telomere-mediated genomic instability in breast tumour cells and in cells from mice lacking breast cancer genes

  • Dr Anuradha Poonepalli, Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
  • Dr Peter McPherson, Department of Pharmocology, University of Toronto, Canada
  • Mr Birendranath Banerjee, Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
  • Mr Aik Kia Khaw, Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
  • Dr Thomas Putti, Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Canada
  • Dr Razq Hakem, Advanced Medical Discovery Institute/Ontario Cancer Institute, University of Toronto, Canada
  • Dr Prakash Hande, Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore

    • BRCA1 and BRCA2 genes have critical roles in major DNA repair pathways and are involved in genomic surveillance through their interaction with different replication, repair and transcription factors. These two genes are known to interact with DNA repair proteins, such as RAD50/MRE11/NBS1 complex and ATM. Studies by us and others have shown that the double strand break repair proteins, such as DNA-PK, Ku80/70 and ATM have a major role in the maintenance of telomere-chromosome stability. It is not known whether BRCA1 and BRCA2 genes play analogous roles in the telomere maintenance and chromosome integrity. In order to study the role of breast cancer genes in with telomere integrity, we have measured telomere length and analysed chromosome instability in Brca1-/- T cells derived from Brca1 conditional knockout mice under either p53-/- or Bcl2 background. Brca1 deficient mouse cells displayed telomere dysfunction in both loss of telomere repeats as well as defective telomere capping. Karyotyping of tBrca1-/-p53-/- cells revealed the presence of telomere dysfunction accompanied by chromosomal translocations. Analysis of archived human breast tumour tissues has revealed shortened telomeres in invasive ductal carcinomas compared to the normal breast tissue from the same patient. Expression of telomerase and telomere-interacting proteins (such as TRF1, TRF2 and POT1) correlated with the tumour progression in breast tumour tissue samples. The telomere dysfunction phenotype in Brca1 deficient cells may suggest that loss of telomere integrity might contribute to chromosome end dysfunction and permit the formation of potentially oncogenic translocations.

    Supported by grants from NUS and NMRC, Singapore.

    Conference Organiser - ICMS Pty Ltd