It is now widely accepted that epigenetic gene silencing is a major driving force in cancer.

Principal Investigator: Dr Andrew Hamilton

It is now widely accepted that epigenetic gene silencing is a major driving force in cancer. Unlike conventional mutations, epigenetic gene silencing involves no change in the primary DNA sequence of a gene. Instead, methylation of cytosine in promoter regions and covalent modification of chromatin proteins such as histones cause the suppression of transcription. Many of these silenced genes are tumour suppressors and promoter/CpG island hypermethylation is frequently associated with poor disease prognosis. Understanding the trigger for these epigenetic changes will be essential to reduce or prevent them occurring.

We are exploring the hypothesis that aberrant production of endogenous siRNA directs the epigenetic silencing of tumour suppressor genes in breast cancer. The background, theoretical and empirical basis for this hypothesis can be summarised thus:

• Epigenetic gene silencing plays a major role in breast cancer
• We know very little of why or how selected genes are initially targeted for epigenetic gene silencing
• There is no well recognised epigenetic mechanism in other systems that might account for initiation specificity
• Recently, RNA interference was shown to be a potentially widespread mechanism of epigenetic silencing-initiation in mammalian cells
• Circumstantial evidence suggests this might be involved in silencing tumour suppressor genes.

The project is broadly in two halves:

1. Detection and cloning of endogenous human siRNA that have sequence homology to selected promoters that are already known to undergo inactivation and hypermethylation in breast cancer.

2. Investigating the function of these siRNA and their relevance to breast cancer.