Rathbone, Victoria Mary; (2024) A study of PTEN-loss driven pathology, oncogenic mechanisms, tissue specificity and therapeutic opportunities. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The PI3K/AKT signalling pathway is a key cellular pathway controlling cell growth, survival and metabolism, and is aberrantly activated in cancer. PTEN is the main negative regulator of this pathway and is one of the most frequently inactivated tumour suppressor genes in sporadic cancer. Germline PTEN mutations underly the rare autosomal-dominant syndrome PTEN hamartoma tumour syndrome (PHTS), which is characterised by benign tumours, neurocognitive defects and an increased risk of specific cancers (i.e. breast, endometrial and thyroid). PHTS offers a unique context in which to study the temporal impact of oncogenic PTEN loss. Mice with a germline PTEN-exon 5 deletion (Pten+/-) are thought to be a relevant model of PHTS. In this thesis we conduct thorough characterisation and trans-species comparison and show convincing concordance between mouse Pten+/- and human PHTS tumours and through this comparison suggest PHTS-specific histopathological findings. Utilising our enhanced understanding of the pathological spectrum of this model, we performed cancer prevention drug-studies with quantitative pathological readouts and identify promising candidate drugs to take forward to clinical testing. We assessed the PTEN status in the tumour development of this model and found that PTEN protein expression is completely lost in specific tumour types, in some cases at very young age, but retained in others, allowing us to propose PTEN as a ‘traditional’ tumour suppressor, only in specific contexts. To elucidate the mechanism of PTEN loss we examined the most penetrant pathology, atypical endometrial hyperplasia, at a transcriptomic, genomic and epigenomic level and present evidence for a non-genomic, pre-transcriptional alternative mechanism of PTEN inactivation. This thesis takes a mouse model of a rare syndrome and utilises it to give insights into PTEN biology and relevance to cancer development, the natural history of oncogenesis in a rare syndrome and therapeutic drug prevention opportunities.

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