Breast cancer tumours can change their behaviour over time, making hormone-blocking drugs stop working. This project will analyse hundreds of stored tumour samples to understand why some breast cancers resist endocrine therapies from the start, and why others develop resistance later. The researchers will examine three aspects of the disease: the physical arrangement of DNA inside tumour cell nuclei, the chemical modifications that switch genes on or off without changing the DNA sequence itself, and a set of proteins called E3-ligases that regulate cell survival. If the work succeeds, it could reveal biological markers that identify non-responders before treatment begins, and point to new drug targets for patients whose tumours are already resistant. The project draws on a tissue bank and clinical database developed at the Edinburgh Breast Unit, combined with expertise at the Edinburgh Cancer Research Centre and MRC Human Genetics Unit.
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The main challenges in current breast cancer therapy are the early and accurate identification of patients whose tumours will not respond to endocrine therapies, the development of treatments for non-responders, and the prevention of endocrine resistance in previously responsive tumours. The Edinburgh Breast Unit has a large patient base, clinical expertise in the area of endocrine resistance, and has developed a tissue bank of over 2000 tumour samples with an associated clinical database. This proposal will draw on this resource and on the considerable scientific expertise available at the Edinburgh Cancer Research Centre and MRC Human Genetics Unit. The program will focus on (i) tumour profiling (ii) epigenetic mechanisms of tumour evolution, and (iii) targeting ubiquitin-ligase pathways. (i) Tumour profiling: We propose integrated and detailed studies of a) the nuclear architecture of tumours at presentation, including levels of chromatin compaction and chromosomal positioning, b) a global analysis of DNA methylation abnormalities, c) micro RNA and mRNA profiling using arrays to focus on the profiles of aromatase resistant tumours (using SNP analysis to exclude genetic gain or loss as an explanation for altered transcription, and mutation analysis), d) protein expression profiling using tissue microarrays to focus on key transforming pathways and epigenetic modulators. (ii) Epigenetic mechanisms of tumour evolution: Studies will focus on a) establishing the mechanisms through which tumour suppressor genes become aberrantly methylated in breast cancer, and b) using novel RNAi screens to identify mechanisms responsible for the development of oestrogen hypersensitivity. (iii) Targeting ubiquitin-ligase pathways: Proteomic and aptamer technologies will be developed for studying a) ubiquitin and ubiquitin-like components in breast cancer, b) the interactions of the MDM2 E3-ligase which is a key regulator of the p53 protein, and c) HERC5, a novel E3-ligase which is up-regulated by letrozole and may be a target for therapy.
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