Dissecting the biomolecular role of Bcl3 in breast cancer metastasis and the design of new interaction inhibitors.

Progression to metastatic disease is usually a devastating event for most cancer patients here in Wales and throughout the world. It is estimated that around 90% of cancer deaths are attributable to poorly treated tumour metastasis, where there are no truly effective drugs in the clinic. In addition, more than 30% of cancer patients will relapse and die because of recurrent metastatic disease despite recent improvements in application of adjuvant therapies.

Bcl3 is a proto-oncogene that plays a key role in regulating gene expression by controlling the activity of transcription factors, such as the NFkB that regulate a variety of cellular genes, including those associated with cell proliferation, apoptosis and the stress response. Bcl3 has been reported to be deregulated in breast cancer but its suppression leads to a reduction in the migratory capacity of the bulk of the tumour cells, with a concomitant increase in migration/metastasis inhibitory genes. Based on these finding Bcl3 was considered as a target for drug development, resulting in some promising therapeutic leads.

The aim of this project is to elucidate the full interaction profile [the interactome] of Bcl3 so as to understand the molecular basis of Bcl3’s contribution to cancer metastasis, which will in turn lead to the development of targeted therapies. We will then combine the identified components with Bcl3 to reconstitute functional complexes and to elucidate their molecular structure using X-ray crystallography and cryo-electron microscopy (cryoEM). The newly gathered structural data will then be used to understand the mechanism of action of recently developed drugs and further the development of next generation drugs for treating cancer metastasis.

As part of the project you will learn a variety of techniques including protein engineering, synthetic biology, structural biology, cell biology and drug discovery to address an important societal and healthcare challenge.

The studentship is available from October 2018