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Title: The role of liver receptor homologue-­1 (LRH-­1) in colorectal cancer
Author: Kramer, Holly
ISNI:       0000 0004 6423 1289
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2015
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The development of colorectal cancer (CRC) occurs sequentially through the accumulation of genetic changes, or mutations, resulting in unrestrained cellular proliferation and survival. The genetic changes leading to CRC are well defined, with aberrant activation of the Wnt signalling pathway and loss of the tumour suppressor p53 playing key roles. This project aimed to investigate the role of the orphan nuclear receptor liver receptor homologue-1 (LRH-1) in the development of CRC. Previous work in this laboratory identified LRH-1 as an important mediator of the estrogen response in breast cancer cells. LRH-1 has also been implicated in the development of CRC, where it promotes cell cycle progression and synergises with β-catenin. Here I provide evidence for novel mutations in the DNA binding domain of LRH-1 in CRC. I found that CRC-associated LRH-1 mutations affect its ability to bind LRH-1 response elements. To better define the mechanisms of LRH-1 action in CRC, gene expression microarray analyses were performed in two CRC cell lines following siRNA-mediated LRH-1 knockdown. Several previously undescribed candidate LRH-1-regulated genes were identified and validated. While I found no evidence for crosstalk between LRH-1 and the Wnt pathway in the CRC cell lines examined, pathway analyses coupled to gene expression profiling suggested a role for LRH-1 in p53 signalling. LRH-1 silencing was shown to be associated with growth inhibition and up-regulation of the cell cycle inhibitor p21 in CRC cells. This occurs in a p53-dependent manner and was not observed in cell lines where p53 is mutated or deleted. I further demonstrated LRH-1-mediated modulation of p53 activity at the p21 promoter. Collectively, this work demonstrates a novel role for LRH-1 in the suppression of p53 signalling in CRC tumours that retain wild-type p53, and identifies LRH-1 as an important prospective target for treatment of these tumours.
Supervisor: Buluwela, Laki ; Ali, Simak Sponsor: Medical Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral