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Title: Epigenomic profiling of oestrogen receptor-positive breast cancer
Author: Patten, Darren
ISNI:       0000 0004 7657 6655
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2017
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Endocrine resistance occurs in the majority of patients who have relapsing breast cancer which remains a challenge to current medical treatment. Tumour heterogeneity poses an obstacle in clinical diagnostics which can lead to suboptimal treatment and the development of therapy resistance. Although tumour heterogeneity, at an intrinsic as well as at an interpatient level, is a potential contributor to endocrine resistance in oestrogen receptor-positive breast cancer, it is not clearly understood. Epigenetically-defined regulatory regions including promoters and enhancers govern cell type specific transcription. In this study, I have processed 47 fresh-frozen primary and metastatic oestrogren receptor-positive breast cancer samples for H3K27ac (acetylation of lysine 27 on histone 3) chromatin immunoprecipitation and high throughput sequencing. The regulatory landscapes of the 47 patient samples were analysed and key regulatory drivers identified. Results demonstrate that although enhancer elements are strongly associated with epigenetic heterogeneity, dominant enhancers tend to be shared across patients. Identified regulatory drivers possess binding sites for the transcription factor YY1 which collaborates with the oestrogen receptor alpha to drive the transcription of several key genes including SLC9A3R1. SLC9A3R1 has subsequently been identified as a novel breast cancer specific oncogene and is shown in this study to stratify oestrogen receptor-positive breast cancer patients. This study demonstrates for the first time that epigenetic annotations can be used to map regulatory, as well as phenotypic, changes through breast cancer progression.
Supervisor: Coombes, Charles ; Magnani, Luca ; Palmieri, Carlo Sponsor: Wellcome Trust ; Breast Cancer Now
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral