Mechanisms of action of ELF5 in breast cancer [thesis]

Catherine Piggin
The ETS transcription factor ELF5 is a critical regulator of cell fate. In the mammary epithelium, ELF5 drives the development of the ER-negative milk-producing alveolar cells, and the balance between ER and ELF5 transcriptional activity is hypothesised to be a fundamental determinant of cell fate. ELF5-driven transcriptional programs may also function in breast cancer, with previous studies demonstrating roles in basal-like and endocrine-resistant disease. The aim of this thesis was to
more » ... ate the transcriptional functions of ELF5 in breast cancer, and the factors that regulate ELF5 activity. A potential mechanism of ELF5 regulation is through alternative splicing, producing unique protein isoforms. There are four ELF5 isoforms; however little is known about their specific functions. ELF5 expression was comprehensively analysed at the isoform level, using RNA-sequencing data from 6,757 Cancer Genome Atlas samples. In breast cancer, ELF5 alterations were subtype-specific, with the basal subtype demonstrating unique isoform expression changes. Despite differences in protein domains, the in vitro functional effects of ELF5 isoforms were similar. Genome-wide sequencing studies were also performed to investigate ELF5 DNA binding sites and transcriptional effects in ER-positive breast cancer cells. ELF5 regulated transcriptional signatures of long-term oestrogen deprivation, suppression of the interferon response, and MYC-regulated gene expression. Increased ELF5 also redistributed the genomic binding sites of the ER pioneer factor FOXA1, representing a novel mechanism by which ELF5 may modulate the oestrogen response. Finally, interactions with other proteins are essential for specific transcriptional regulation. However, no ELF5-interacting proteins have previously been identified in human breast cancer cells. The protein interactions of chromatin-bound ELF5 were investigated using RIME, identifying DNA-PKcs. A transcriptional model involving ELF5, ER and DNA-PKcs was proposed, with important potential implicati [...]
doi:10.26190/unsworks/3362 fatcat:zytyw2vdwzeedjqsnaawvcw354