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1. Exploring the role of LRH-1 in cancer progression. The orphan nuclear receptor, Liver Receptor Homologue 1 (LRH-1) has been implicated in breast cancer progression via 2 mechanisms. Firstly by stimulating expression of cell cycle associated genes, and secondly by increasing oestrogen synthesis, thereby promoting growth of oestrogen-dependent tumours. To fully understand the effects of LRH-1 in breast cancer, we have developed a breast cancer cell line that inducibly expresses LRH-1 in response to doxycycline. This project will examine the effects of increased LRH-1 expression on various parameters of breast cancer progression, including cell proliferation, invasion, and gene expression. 2. Transgenic model of LRH-1 – induced epithelial proliferation Supervisors: Dr Colin Clyne, Dr. Ashwini Chand LRH-1 is expressed in approximately 50% of primary human breast cancers, but is not expressed in normal breast epithelium. To understand the effects of increased LRH-1 expression in breast, we have created a transgenic mouse that expresses human LRH-1 specifically in mammary epithelium, in response to doxycycline. Using this system, LRH-1 protein levels in breast can be controlled with precision. We are using this mouse to examine the effects of LRH-1 on mammary gland development, epithelial cell proliferation, and tumour formation. 3. LRH-1 antagonists as a novel breast cancer therapy Supervisor: Dr Ashwini Chand The orphan nuclear receptor, Liver Receptor Homologue 1 (LRH-1) is involved in breast cancer progression. Finding an inhibitor of LRH-1 function could be a useful breast cancer therapy. We have used in silico screening approaches to identify novel compounds that act as LRH-1 antagonists. Using breast cancer cell lines and mouse models, the project will examine the efficacy and specificity of these inhibitors in vitro using assays of cell proliferation, invasiveness and metastasis. 4. LKB1: a link between obesity and breast cancer Supervisors: Dr Kristy Brown Breast cancer risk is significantly increased with obesity, although the mechanisms underlying this association are not known. The serine-threonine kinase LKB1 plays an important role in a wide variety of physiological processes, including fat metabolism and breast tumorigenesis. One of the targets of LKB1, AMP kinase, mediates fatty acid synthesis. AMP kinase also phosphorylates and inhibits transcriptional cofactors that mediate oestrogen synthesis in breast adipose tissue, which in turn influences breast cancer risk. Our work aims to characterise the regulation of LKB1 expression and activity by the altered hormonal milieu of menopause, thereby providing a critical link between obesity and breast cancer. 5. Epigenetic regulation of genes involved in breast cancer Supervisor: Dr Kevin Knower Development of breast cancer is characterised by a variety of genetic lesions including gene amplifications and deletions, point mutations, chromosomal rearrangements and overall aneuploidy. However, one of the most common molecular alterations in cancer is epigenetic change. Epigenetics describes a trait that is heritable, yet not based upon a change in primary DNA sequence. These epigenetic changes occur at a higher frequency than genetic changes, occur at defined regions in a gene, and most importantly are reversible upon treatment with pharmacological agents. DNA methylation is one well known epigenetic-mechanism that has a clear synergy with alterations in gene regulation that is associated with the onset of a developing cancer. This project will investigate the epigenetic regulation, including DNA methylation, of genes known to have an important role in breast cancer, including Aromatase and LRH-1. The project aims to identify changes in epigenetic status between normal and cancerous tissue to give a clearer understanding and development of future pharmacological agents. 6. Transcriptional silencing of LRH-1 in ovarian Granulosa Cell Tumors. Supervisor: Dr. Nick Fleming, Dr Colin Clyne This decade has witnessed the discovery of the miRNA genes which act as a further layer of regulation within biological systems and emerging evidence suggests that their functions are dysregulated in cancer. Importantly, miRNA genes lend themselves to therapeutic utilisation. LRH-1 has been identified as a target of miRNA regulation whereas is its close homolog, SF-1, appears to lack such regulation. We have previously shown that Granulosa Cell Tumours (GCT) express the gene for LRH-1 but lack LRH-1 activity. The aim of this project is to determine whether miRNA regulation is the cause of LRH1 deactivation in GCT. 7. Sirtuins and breast cancer Supervisor: Dr. Izabella Czajka-Oraniec SIRT1 and SIRT2 are members of the family of NAD+ - dependent protein deacetylases that have important roles in numerous physiological processes such as transcription, cell survival and apoptosis, DNA repair, gene silencing and cell cycle regulation. Their roles in endocrine signalling, metabolism and age related cancers are now widely investigated. Resveratrol, a phytoestrogen in grapes and wine, was found to suppress growth of breast cancer and to inhibit aromatase expression in breast cancer cells. As resveratrol is a potent activator of SIRT1, our project aims to determine if SIRT1 and SIRT2 are involved in regulation of aromatase expression and activity in breast cancer cells and adipose stromal cells and to identify possible pathways leading to aromatase regulation. We aim also to identify whether 17β-estradiol, tumour derived substances such as PGE2 and hormones released by adipose tissue (adiponectin, leptin) could be involved in the regulation of SIRT1 and SIRT2 levels or their enzymatic activity in breast cancer and breast adipose stromal cells. |
