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Brca2 deficiency in the murine small intestine sensitizes to p53-dependent apoptosis and leads to the spontaneous deletion of stem cells

Oncogene volume 24, pages 3842–3846 (2005)Cite this article

Abstract

The gene encoding the human BRCA2 tumour suppressor is mutated in a number of different tumour types, most notably inherited breast cancers. The primary role of BRCA2 is thought to lie in the maintenance of genomic stability via its role in the homologous recombination pathway. We generated mice in which Brca2 was deleted from virtually all cells within the adult small intestine, using a CYP1A1-driven Cre-Lox approach. We noted a significant p53-dependent increase in the levels of spontaneous apoptosis which persisted for several months after removal of the gene and ultimately we observed the spontaneous deletion of Brca2-deficient stem cells. Brca2 deficiency did not lead to gross changes in intestinal physiology but did enhance sensitivity to a variety of DNA crosslinking agents. Taken together, our results indicate that Brca2 plays an important role in the response to DNA damage in the small intestine. Furthermore, we show that Brca2 deficiency results in the spontaneous deletion of stem cells, thereby protecting the small intestine against tumorigenesis.

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Acknowledgements

We thank Professor Tak Mak of the University of Toronto, Canada, for the generous donation of mice bearing the floxed Brca2 allele. We also acknowledge Mark Bishop and Derek Scarborough for valuable technical assistance. This work was supported by CR-UK, AICR and Wales Gene Park.

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  1. School of Biosciences, Cardiff University, Museum Avenue, Cardiff, CF10 3US, UK

    Trevor Hay, Teresa Patrick, Owen J Sansom & Alan R Clarke

  2. Cambridge Institute for Medical Research, Addenbrookes Hospital, Cambridge, CB2 2XY, UK

    Douglas Winton

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  1. Trevor Hay
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Hay, T., Patrick, T., Winton, D. et al. Brca2 deficiency in the murine small intestine sensitizes to p53-dependent apoptosis and leads to the spontaneous deletion of stem cells. Oncogene 24, 3842–3846 (2005). https://doi.org/10.1038/sj.onc.1208533

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