Colorectal cancer is one of the most clinically significant types of cancer due to both high incidence and mortality. Despite the well-established role of aberrant Wnt signalling in initiation and progression of colorectal cancer, therapies that specifically target the Wnt pathway are exceptionally limited. The development of such therapies is, in part, restricted by the toxicity of Wnt signalling inhibition for adult tissue homeostasis. Given this limitation, therapies that target downstream components and target genes of the Wnt pathway are required to minimise potential toxicity. The chromatin remodelling ATPase subunit Brg1 has been found to interact with β-catenin and facilitate transcriptional program driven by the Wnt pathway. In this thesis I aimed to explore Brg1’s potential as a therapeutic target in Wnt driven intestinal tumourigenesis. To achieve this, I conditionally deleted Brg1 in the murine small intestinal epithelium under normal physiological conditions and in the context of aberrant Wnt signalling using a range of transgenic mouse models. Additionally, I investigated the potential toxicity of Brg1 inhibition by analysing the effects of Brg1 loss in a range of epithelial tissues from the gastrointestinal tract and bladder. The results presented in this thesis demonstrate that Brg1 deficiency impedes Wnt-driven tumourigenesis in the murine small intestinal epithelium via attenuation of Wnt signalling and the elimination of stem cell derived tumours, which have a higher tumourigenic potential. Additionally, Brg1 was found to play a major role in the maintenance of normal small intestinal stem cell homeostasis, as loss of Brg1 in the small intestinal epithelium resulted in ablation of the stem cell population. The impact of Brg1 deficiency on homeostasis of other tissues of the gastrointestinal tract and bladder exhibited a remarkable diversity, from induction of epithelial hyperplasia to very subtle alterations in cell differentiation. Overall, the results presented in this thesis portray Brg1 as a promising potential therapeutic target in Wnt-driven neoplasia and suggest that specific targeting of the Brg1/β-catenin interaction rather than the catalytic activity of Brg1 may help to avoid any Wnt-independent toxicity of Brg1 inhibition.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:567272 |
| Date | January 2012 |
| Creators | Holik, Aliaksei |
| Publisher | Cardiff University |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://orca.cf.ac.uk/24034/ |
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