Signal Transduction Group
This project aims to investigate the role of the Promyelocytic Leukemia gene (PML) in triple negative breast cancer (TNBC). PML is very well known for its tumour-suppressive functions, however, in TNBC, PML is over-expressed and acts as an oncogene, and the reasons of this unusual behaviour are still largely unknown. We will investigate the mechanisms that lead to PML over-expression in a large cohort of breast cancer samples. The data obtained by these analyses will provide clinical correlation of underlying biology. Using several TNBC cellular models, we will test wether PML over-expression occurs in a transcriptional dependent-manner or it occurs at proteins levels through the alteration of its ubiquitin/degradation pathway. PML forms distinct structures into the nucleus known as PML Nuclear Bodies (PML-NBs). Despite the pivotal roles of PML-NBs in cell physiology, their composition has been elusive and PML-NBs have not yet been characterised. Through a new methodology (RIME) that combines chromatin/protein-complexes purification and mass spectrometry analysis, we will purify and characterise the PML-NBs of TNBC for the first time. These studies, will share light on the composition of the PML-NBs in TNBC, elucidating their role in TNBC and opening new opportunity to discovery new potential targets for TNBC therapy. Finally, we want to propose to use arsenic trioxide (ATO) for TNBC treatment. ATO binds directly to PML, and it is the drug of choice for the treatment of Acute Promyelocytic Leukemia (APL), caused by the fused oncoprotein PML-RARA, and induces the complete regression of the disease. We propose to study in vitro and in vivo the effect of ATO in TNBC. We reason that, since PML is over-expressed only in TNBC, ATO treatment will show a selective effect only in TNBC. We will initially test the effect of ATO on a large panel of breast cancer cell lines and we will then further characterise ATO treatment in a series of xenografts experiments. These experiments will determine the efficacy of ATO treatment in vitro and in vivo in TNBC. Future studies will be directed to propose ATO for treatment of TNBC patients.
- Suitable for Honours or PhD student