Ubiquitination is one of the most abundant protein modifications in cellular signaling, controlling numerous pathways such as cell cycle progression, DNA damage response, and transcription. Defects in either the Ubiquitin (Ub) conjugation pathway, or downstream effectors of Ub signaling, are linked with cancer pathogenesis. Accordingly, components of the Ub-proteasome system, and E3 ligases in particular, have become an attractive target for development of novel therapeutic strategies to combat cancer. The E3 ligase UBR5 (EDD) has biological roles with clear relevance to cancer (DNA damage, etc), but in many cases the underlying biochemistry of these roles is poorly understood.
Analysis of a cohort of breast cancer patients showed that increased UBR5 expression was significantly associated with decreased breast cancer specific survival and disease free survival, presenting the first evidence of an adverse prognostic significance of UBR5 expression in primary breast cancer. To further explore the biological role of UBR5 in breast cancer we have developed a suite of cell culture and animal models with inducible UBR5 expression or harbouring mutations in UBR5 functional domains. We are now coupling these models with various genetic and proteomics approaches to define E3 ligase substrates, and effects on cell proliferation, migration and tumour growth.