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IN VIVO VALIDATION OF THE PRL PHOSPHATASES AS THERAPEUTIC TARGETS IN CANCER USING NOVEL ANIMAL MODEL SYSTEMS
The PRLs are a subfamily of dual specificity phosphatases that appear to play important roles in oncogenesis. Much of the current understanding of PRL function has been either correlative, and deduced from observed PRL overexpression in pathological conditions, or from in vitro analysis of signaling pathways following PRL deletion or overexpression. Such studies, necessitated by the general lack of synthetic inhibitors or compounds to probe the substrate specificity and biological interactions of the PRLs, are nonetheless now providing critical insight into potential biological substrates and roles of the PRL phosphatases. The recent identification of PTEN as a substrate for PRL2 provided the foundation for studies to further define the role of PRL2 in oncogenesis and, by analogy, the normal physiological function of PRL2. In the studies described herein, a novel PRL2 conditional knock-out animal was generated and used to validate the PRL2/PTEN interaction in a leukemic phenotype, and further demonstrated that PRL2 inhibition can restore dysregulated PTEN/AKT pathways to significantly attenuate disease progression. Inhibition of PRL2 therefore represents a novel potential therapeutic strategy in the management and treatment of AML. This thesis project also sought to further examine the role of the PRLs in oncogenesis through their regulation and interaction of targets within the TME. Functional analyses revealed that PRL3 was the only PRL to have a prominent role in host response to TME development, and that previously proposed roles for PRL3 in angiogenesis and immune cell recruitment is dependent upon PRL3 expression and activity in cells external to the TME. The study also revealed a previously unrecognized synergism between VEGF and PRL3 in the host in promoting TME angiogenesis. The studies of PRL3 in the TME suggest the potential physiological role of PRL3 in wound healing.
- Doctor of Philosophy
- West Lafayette