Novel Cancer models: investigating tumorigenic potential of PTEN mutations

Cellular functions are regulated by a coordinate and subsequent series of events mainly involving proteins and lipids. The PI3-kinase/PTEN signalling pathway plays an important role in regulation of cell growth, survival, metabolism and migration in many cells. Aberrations in this pathway have implications in metabolic and hyper-proliferative disorders such as diabetes and cancer. PTEN is a tumour suppressor found mutated at high frequency in many primary and metastatic human cancers. PTEN has both lipid and protein phosphatase activities. It is known that PTEN can antagonize the PI3K/Akt pathway by dephosphorylating phosphatidyl-inositol 3,4,5 triphosphate (PIP3), the primary product of PI3K and thereby acts as a tumour suppressor. Previous studies in our lab have established that both protein and lipid phosphatase activities are required for PTEN to inhibit cellular invasion and to mediate most of its largest effects on gene expression.
Most of PTENs tumour suppressor activities have been attributed to its ability to regulate signalling downstream of AKT. However, our recent data have shown that two PTEN mutants PTEN-Y138L and PTEN-R308C, can regulate AKT phosphorylation and signalling downstream but fail to regulate processes such as cell invasion and epithelial cell architecture. This suggests that in some circumstances the regulation not of AKT, but of signalling mechanisms that control invasion can correlate with PTEN-mediated tumour suppression. To further understand how PTEN could regulate tumorigenesis, two transgenic knock in mice lines were developed expressing PTEN-Y138L and PTEN-R308C mutants. The main aim of my project is to investigate if these PTEN mutants lead to tumour formation. Y138L mutation resulted in early embryonic lethality and heterozygous mice develop tumour between 5 and 8 months. R308C heterozygous and homozygous mice are both viable instead but preliminary data suggest that the mutation may cause an increase in the body weight.
Analyses using these mice will also enable me to understand the mechanisms by which these mutants promote tumour development and test whether we can make predictions about how to match particular patients with drugs to help inform cancer treatment decisions.