PTEN is a dual protein lipid phosphatase frequently inactivated in a variety of tumor predisposition syndromes, the PTEN hamartoma tumor syndrome (PHTS), and in sporadic cancer. It has long been known that PTEN deletion or functional loss drives tumorigenesis in multiple tissues through hyper-activation of the PI3K-Akt-mTOR pathways; however, new and important PI3K-independent activities, mainly related to PTEN nuclear localization, have been recently included in the repertoire of the protein's tumor suppressive functions. Our own previous studies have highlighted the deleterious and tissue-specific consequences of subtle reductions in PTEN levels on tumor initiation and progression, findings with important implications for cancer prevention and therapy. This new knowledge suggests an unexpected level of complexity and subtlety in the PTEN protein's activity and regulation, far beyond its canonical oncosuppressive role through repression of the PI3K pathway, which could explain the relatively low efficacy of the various PI3K inhibitors so far tested as single agents in PTEN deficient tumors. We therefore propose to further characterize the biological function of PTEN both in vivo and in vitro, with the following specific aims:
Aim 1 To explore the relative contribution of lipid and protein phosphatase-dependent and -independent tumor suppressive functions of PTEN in vivo: We will study tumor onset, incidence, and progression, as well as PTEN mechanisms of action, in two different KI mouse models, each harboring a phosphatase-dead mutation PtenC124S, or a lipid phosphatase-dead mutation PtenG129E.
Aim 2 - To investigate the impact of aberrant PTEN localization on tumor initiation and progression: We will take advantage of a specific KI mouse model expressing a mutant form of PTEN (PtenK289E) in order to define the role of nuclear functions of PTEN in vivo and in vitro.
Aim 3 - To define the role of miRNA-mediated PTEN regulation in tumorigenesis: We will investigate the oncogenic potential of novel PTEN-targeting miRNAs by studying transgenic mouse models that we have recently generated for this purpose.
Aim 4 - To explore mechanisms involved in transcriptional and epigenetic regulation of PTEN in breast cancer: We will examine the involvement of retinoic acid receptor (RAR)- and TET- dependent transcriptional and epigenetic regulation of PTEN expression in normal and pathological settings. This investigation will ultimately lead to a deeper knowledge of the function of PTEN in normal and pathological conditions, facilitating the rational design of novel approaches to cancer prevention and therapy.
Genetic loss, down-regulation, and mutations of the phosphatase and tensin homolog (PTEN) gene are frequently described in various types of cancer. This proposal outlines different experimental strategies to probe how modulation of the levels, specific functions and localization of PTEN can differentially affect certain oncosuppressive pathways but not others, and may be responsible for distinctive and tissue-specific oncogenic outcomes. We will use mouse models and cell lines in culture to identify new mechanisms, pathways/signatures and novel biomarkers essential to stratifying patients on genetic and molecular bases, as well as facilitate the design of novel and more tailored combinational therapies directed toward the ultimate goal of cancer eradication.
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