Regulation of Brk/PTK6 Expression in Breast Cancer Cell Lines

Brk/PTK6 is an intracellular tyrosine kinase whose expression is up-regulated in many breast cancers and high expression has been linked to higher tumour grade. It has been shown to potentiate EGF, IGF and MET signalling pathways resulting in increased
signalling up-regulating several processes that are required for tumour development such as cellular proliferation, anchorage-independent cell growth and migration. Brk expression also results in decreased cell death. Much of the current research focuses on identifying new substrates and elucidating Brk's potential role in tumour progression and chemotherapy resistance. However, to
date there is little known about the processes that lead to Brk expression. Identification of a HIF-response element upstream of the ptk6 gene indicates that hypoxia could play a role in regulating expression, although this is unlikely to be the only mechanism. Understanding how Brk expression is regulated may lead to the identification of new targets for therapeutic intervention.

This project will focus on identifying transcription factors that are known to be involved in tumourigenesis and investigating whether they play a role in regulating Brk expression. Expression analysis will be carried out to identify transcription factor expression patterns in breast cancer cell lines which can then be correlated to Brk expression. Once individual transcription factors (or their families) have been identified, RNA interference and over expression techniques will be used to down regulate transcription factor expression and the effects on Brk expression will be determined.  In addition methylation of the Brk promoter in breast cancer cells with varied Brk expression will be examined The main techniques for this study will be cell culture, RNA interference, RT-PCR, RNA extraction, reverse transcription, western blotting and epigenetic analysis.

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This is a self funded topic

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