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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Molecular Oncogenesis Study Section (MONC)
Program Officer
Mietz, Judy
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Beth Israel Deaconess Medical Center
United States
Zip Code
Matsumoto, Akinobu; Pasut, Alessandra; Matsumoto, Masaki et al. (2017) mTORC1 and muscle regeneration are regulated by the LINC00961-encoded SPAR polypeptide. Nature 541:228-232
Noguera, Nélida Inés; Piredda, Maria Liliana; Taulli, Riccardo et al. (2016) PML/RARa inhibits PTEN expression in hematopoietic cells by competing with PU.1 transcriptional activity. Oncotarget 7:66386-66397
Tay, Yvonne; Pandolfi, Pier Paolo (2016) Posttranscriptional Regulation of PTEN by Competing Endogenous RNAs. Methods Mol Biol 1388:139-54
Poliseno, Laura; Pandolfi, Pier Paolo (2015) PTEN ceRNA networks in human cancer. Methods 77-78:41-50
Lunardi, Andrea; Varmeh, Shohreh; Chen, Ming et al. (2015) Suppression of CHK1 by ETS Family Members Promotes DNA Damage Response Bypass and Tumorigenesis. Cancer Discov 5:550-63
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
Lunardi, Andrea; Webster, Kaitlyn A; Papa, Antonella et al. (2014) Role of aberrant PI3K pathway activation in gallbladder tumorigenesis. Oncotarget 5:894-900
Tay, Yvonne; Rinn, John; Pandolfi, Pier Paolo (2014) The multilayered complexity of ceRNA crosstalk and competition. Nature 505:344-52
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
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

Showing the most recent 10 out of 38 publications