PTEN, a phosphatase that opposes the PI3K/AKT pathway, was discovered as the tumor-suppressor on the frequently mutated 10q23 locus. Inherited PTEN mutations are also found in three related autosomal dominant disorders characterized by tumor susceptibility and developmental defects. Our continuing efforts have shown that Pten inactivation in the mouse results in early embryonic lethality and that Pten acts as a bona fide haploinsufficient tumor suppressor. Ongoing studies in the lab demonstrate that subtle reductions in the function of PTEN due to mutation, reduced gene expression and changes in subcellular localization have catastrophic consequences for cancer development. We propose to determine the consequences of aberrant PTEN regulation and its altered levels of expression in tumorigenesis and ontogenesis through a direct genetic approach in the mouse with the following aims: 1) To explore the role of subtle PTEN dose variation in tumorigenesis and ontogenesis. We have generated a hypomorphic Pten allelic series in the mouse. This series of mutant mice are born with decreasing Pten levels. We have also recently generated transgenic mice that express Pten above normal systemic levels. We propose to study the consequences of these subtle changes for the initiation and progression of cancer, embryonic development and for the aging process. 2) To define the role of miRNA-mediated, post-transcriptional regulation of PTEN in tumorigenesis. MicroRNAs (miRNAs) have recently come into focus as novel post-transcriptional regulatory elements. Since subtle variations in PTEN profoundly alter cancer progression, we hypothesized that PTEN may be a relevant target for oncogenic miRNAs. Accordingly, we have found a new PTEN-targeting proto-oncogenic miRNA locus. The current proposal aims at studying the functional cross-talk between this locus and PTEN both in vitro as well and in vivo in transgenic and KO models. 3) To determine the causal relationship and functional consequences of aberrant localization of PTEN in human tumorigenesis, cancer susceptibility and embryonic development. Germline missense mutation at codon 289 (AAA to GAA, Lys to Glu) was detected in a family with Cowden disease. We have previously reported that PTENK289E mutant retains its full enzymatic activity but fails to accumulate in nuclei of patient tissue due to a nuclear import defect. We will generate PtenK289E knock-in mice to better understand the functional and causal significance of this lysine mutant. Analysis of these mutant mice and derived primary cells will allow us to unravel the tumor suppressive and developmental roles of nuclear Pten. 4) To assess in a systematic high-throughput manner the consequence of functional PTEN mutations in vivo in the mouse. PTEN mutations result in nonsense, frameshift or splicing mutations leading to protein truncation. However, up to 30% of PTEN point mutations conserve the full-length protein. Several of these mutations influence PTEN protein stability, function and localization. We have devised a strategy to model these mutations in a "high-throughput" in vivo manner. NARRATIVE PTEN is the most commonly mutated tumor suppressor genes in human cancer. Ongoing studies in the lab demonstrate that subtle reduction in the function of PTEN due to mutation, reduced gene expression and changes in subcellular localization can have catastrophic consequences for cancer development. We propose to determine the molecular mechanisms by which PTEN function and levels are normally modulated and study the consequences of aberrant PTEN regulation and its altered levels of expression in ontogenesis and tumorigenesis through a direct genetic approach in the mouse.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Cancer Molecular Pathobiology Study Section (CAMP)
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Mietz, Judy
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Beth Israel Deaconess Medical Center
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Tay, Yvonne; Tan, Shen Mynn; Karreth, Florian A et al. (2014) Characterization of dual PTEN and p53-targeting microRNAs identifies microRNA-638/Dnm2 as a two-hit oncogenic locus. Cell Rep 8:714-22
Papa, Antonella; Wan, Lixin; Bonora, Massimo et al. (2014) Cancer-associated PTEN mutants act in a dominant-negative manner to suppress PTEN protein function. Cell 157:595-610
Lunardi, Andrea; Webster, Kaitlyn A; Papa, Antonella et al. (2014) Role of aberrant PI3K pathway activation in gallbladder tumorigenesis. Oncotarget 5:894-900
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Song, Su Jung; Pandolfi, Pier Paolo (2014) miR-22 in tumorigenesis. Cell Cycle 13:11-2
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Tay, Yvonne; Karreth, Florian A; Pandolfi, Pier Paolo (2014) Aberrant ceRNA activity drives lung cancer. Cell Res 24:259-60
Morotti, A; Panuzzo, C; Crivellaro, S et al. (2014) BCR-ABL disrupts PTEN nuclear-cytoplasmic shuttling through phosphorylation-dependent activation of HAUSP. Leukemia 28:1326-33
González-Billalabeitia, Enrique; Seitzer, Nina; Song, Su Jung et al. (2014) Vulnerabilities of PTEN-TP53-deficient prostate cancers to compound PARP-PI3K inhibition. Cancer Discov 4:896-904
Song, Su Jung; Poliseno, Laura; Song, Min Sup et al. (2013) MicroRNA-antagonism regulates breast cancer stemness and metastasis via TET-family-dependent chromatin remodeling. Cell 154:311-24

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