PI(3)King Apart PTEN's Role in Cancer

The tumor suppressor phosphatase and tensin homolog (PTEN) is a nonredundant phosphatase, counteracting one of the most critical cancer-promoting pathways: the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. In addition to the canonical function of dephosphorylation of phosphatidylinositol-3,4,5-trisphosphate (PIP3), recent studies showed the intriguing roles of PTEN in regulating genomic instability, DNA repair, stem cell self-renewal, cellular senescence, and cell migration and/or metastasis. Clinically, PTEN mutations and deficiencies are prevalent in many types of human cancers. Severe PTEN deficiency is also associated with advanced tumor stage and therapeutic resistance, such as the resistance to trastuzumab, an anti-HER2 therapy. Currently, targeting the deregulated PI3K/PTEN-Akt signaling axis has emerged as one of the major tenets in anticancer drug development. In this review, we highlight our current knowledge of PTEN function and the recent discoveries in dissecting the PTEN signaling pathway. The deregulations of PTEN in cancers, clinical lessons, and new prospects of rationally designed PI3K/Akt-targeted therapy for effective cancer treatment are also discussed. Clin Cancer Res; 16(17); 4325–30. ©2010 AACR.

[1]  M. Loda,et al.  Identification of the miR-106b~25 MicroRNA Cluster as a Proto-Oncogenic PTEN-Targeting Intron That Cooperates with Its Host Gene MCM7 in Transformation , 2010, Science Signaling.

[2]  H. Lane,et al.  Specific apoptosis induction by the dual PI3K/mTor inhibitor NVP-BEZ235 in HER2 amplified and PIK3CA mutant breast cancer cells , 2009, Proceedings of the National Academy of Sciences.

[3]  G. Robertson,et al.  Tumor Suppression by PTEN Requires the Activation of the PKR-eIF2α Phosphorylation Pathway , 2009, Science Signaling.

[4]  C. Croce,et al.  miR-221&222 regulate TRAIL resistance and enhance tumorigenicity through PTEN and TIMP3 downregulation. , 2009, Cancer cell.

[5]  R. Pieper,et al.  A novel PTEN-dependent link to ubiquitination controls FLIPS stability and TRAIL sensitivity in glioblastoma multiforme. , 2009, Cancer research.

[6]  Metin N. Gurcan,et al.  Pten in Stromal Fibroblasts Suppresses Mammary Epithelial Tumors , 2009, Nature.

[7]  Barry Fine,et al.  Activation of the PI3K Pathway in Cancer Through Inhibition of PTEN by Exchange Factor P-REX2a , 2009, Science.

[8]  Yiling Lu,et al.  Rak functions as a tumor suppressor by regulating PTEN protein stability and function. , 2009, Cancer cell.

[9]  Violeta Serra,et al.  Phosphatidylinositol 3-kinase hyperactivation results in lapatinib resistance that is reversed by the mTOR/phosphatidylinositol 3-kinase inhibitor NVP-BEZ235. , 2008, Cancer research.

[10]  Gerald C. Chu,et al.  P53 and Pten control neural and glioma stem/progenitor cell renewal and differentiation , 2008, Nature.

[11]  K. Shokat,et al.  A chemical screen in diverse breast cancer cell lines reveals genetic enhancers and suppressors of sensitivity to PI3K isoform-selective inhibition. , 2008, The Biochemical journal.

[12]  Y. Yin,et al.  PTEN: a new guardian of the genome , 2008, Oncogene.

[13]  I. Batty,et al.  Understanding PTEN regulation: PIP2, polarity and protein stability , 2008, Oncogene.

[14]  P. Pandolfi,et al.  Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer. , 2008, The Journal of clinical investigation.

[15]  Alice T. Loo,et al.  PTEN-deficient cancers depend on PIK3CB , 2008, Proceedings of the National Academy of Sciences.

[16]  Pier Paolo Pandolfi,et al.  The deubiquitinylation and localization of PTEN are regulated by a HAUSP–PML network , 2008, Nature.

[17]  M. Varella‐Garcia,et al.  Multi-genetic events collaboratively contribute to Pten-null leukaemia stem-cell formation , 2008, Nature.

[18]  Pier Paolo Pandolfi,et al.  Tenets of PTEN Tumor Suppression , 2008, Cell.

[19]  Sanjay Goel,et al.  PIK3CA mutation/PTEN expression status predicts response of colon cancer cells to the epidermal growth factor receptor inhibitor cetuximab. , 2008, Cancer research.

[20]  G. Mills,et al.  Improved classification of breast cancer by analysis of genetic alterations and gene expression profiling , 2011 .

[21]  G. Mills,et al.  Preclinical Testing of Clinically Applicable Strategies for Overcoming Trastuzumab Resistance Caused by PTEN Deficiency , 2007, Clinical Cancer Research.

[22]  K. Ghoshal,et al.  MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer. , 2007, Gastroenterology.

[23]  Lewis C. Cantley,et al.  AKT/PKB Signaling: Navigating Downstream , 2007, Cell.

[24]  Hong Wu,et al.  Identification of the JNK signaling pathway as a functional target of the tumor suppressor PTEN. , 2007, Cancer cell.

[25]  S. Stein,et al.  Lapatinib antitumor activity is not dependent upon phosphatase and tensin homologue deleted on chromosome 10 in ErbB2-overexpressing breast cancers. , 2007, Cancer research.

[26]  P. Pandolfi,et al.  Essential Role for Nuclear PTEN in Maintaining Chromosomal Integrity , 2007, Cell.

[27]  P. Pandolfi,et al.  NEDD4-1 Is a Proto-Oncogenic Ubiquitin Ligase for PTEN , 2007, Cell.

[28]  W. Yung,et al.  Mitogen-activated Protein Kinase Kinase-4 Promotes Cell Survival by Decreasing PTEN Expression through an NFκB-dependent Pathway* , 2006, Journal of Biological Chemistry.

[29]  H. Ressom,et al.  Activation of p53-Dependent Growth Suppression in Human Cells by Mutations in PTEN or PIK3CA , 2006, Molecular and Cellular Biology.

[30]  Xi C. He,et al.  PTEN maintains haematopoietic stem cells and acts in lineage choice and leukaemia prevention , 2006, Nature.

[31]  S. Morrison,et al.  Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells , 2006, Nature.

[32]  D. Geschwind,et al.  PTEN negatively regulates neural stem cell self-renewal by modulating G0-G1 cell cycle entry. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[33]  Chien-Hsing Lu,et al.  Mechanisms of Trastuzumab Resistance and Their Clinical Implications , 2005, Annals of the New York Academy of Sciences.

[34]  Jason A. Koutcher,et al.  Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis , 2005, Nature.

[35]  A. Yoshimura,et al.  Reduction of PTEN protein and loss of epidermal growth factor receptor gene mutation in lung cancer with natural resistance to gefitinib (IRESSA) , 2005, British Journal of Cancer.

[36]  R. Parsons,et al.  PTEN Loss Inhibits CHK1 to Cause Double Stranded-DNA Breaks in Cells , 2005, Cell cycle.

[37]  T. Pandita,et al.  Lack of PTEN sequesters CHK1 and initiates genetic instability. , 2005, Cancer cell.

[38]  Johan Auwerx,et al.  Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity , 2004, Nature.

[39]  C. Downes,et al.  PTEN function: how normal cells control it and tumour cells lose it. , 2004, The Biochemical journal.

[40]  Ming Tan,et al.  PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. , 2004, Cancer cell.

[41]  A. Hall,et al.  Regulation of Cell Migration by the C2 Domain of the Tumor Suppressor PTEN , 2004, Science.

[42]  J. Fata,et al.  Insulin-like Growth Factor-II Regulates PTEN Expression in the Mammary Gland* , 2003, Journal of Biological Chemistry.

[43]  Hong Wu,et al.  PTEN tumor suppressor regulates p53 protein levels and activity through phosphatase-dependent and -independent mechanisms. , 2003, Cancer cell.

[44]  Richard A. Firtel,et al.  Spatial and Temporal Regulation of 3-Phosphoinositides by PI 3-Kinase and PTEN Mediates Chemotaxis , 2002, Cell.

[45]  C. Eng,et al.  Protean PTEN: form and function. , 2002, American journal of human genetics.

[46]  T. Mustelin,et al.  The Egr-1 transcription factor directly activates PTEN during irradiation-induced signalling , 2001, Nature Cell Biology.

[47]  T. Mak,et al.  Regulation of PTEN transcription by p53. , 2001, Molecular cell.

[48]  I. Pass,et al.  Tumor suppressor and anti-inflammatory actions of PPARγ agonists are mediated via upregulation of PTEN , 2001, Current Biology.

[49]  H. Hanafusa,et al.  Stabilization and productive positioning roles of the C2 domain of PTEN tumor suppressor. , 2000, Cancer research.

[50]  L. Schriml,et al.  Mutational spectra of PTEN/MMAC1 gene: a tumor suppressor with lipid phosphatase activity. , 1999, Journal of the National Cancer Institute.

[51]  Tomohiko Maehama,et al.  Crystal Structure of the PTEN Tumor Suppressor Implications for Its Phosphoinositide Phosphatase Activity and Membrane Association , 1999, Cell.

[52]  José Luis de la Pompa,et al.  Negative Regulation of PKB/Akt-Dependent Cell Survival by the Tumor Suppressor PTEN , 1998, Cell.

[53]  Kenneth M. Yamada,et al.  Inhibition of cell migration, spreading, and focal adhesions by tumor suppressor PTEN. , 1998, Science.

[54]  Tomohiko Maehama,et al.  The Tumor Suppressor, PTEN/MMAC1, Dephosphorylates the Lipid Second Messenger, Phosphatidylinositol 3,4,5-Trisphosphate* , 1998, The Journal of Biological Chemistry.

[55]  M. Wigler,et al.  P-TEN, the tumor suppressor from human chromosome 10q23, is a dual-specificity phosphatase. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[56]  Hong Sun,et al.  TEP1, encoded by a candidate tumor suppressor locus, is a novel protein tyrosine phosphatase regulated by transforming growth factor beta. , 1997, Cancer research.

[57]  Jing Li,et al.  Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome , 1997, Nature Genetics.

[58]  W. K. Alfred Yung,et al.  Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers , 1997, Nature Genetics.

[59]  M. Wigler,et al.  PTEN, a Putative Protein Tyrosine Phosphatase Gene Mutated in Human Brain, Breast, and Prostate Cancer , 1997, Science.

[60]  L. Saal,et al.  Recurrent gross mutations of the PTEN tumor suppressor gene in breast cancers with deficient DSB repair , 2008, Nature Genetics.

[61]  J. Kurie,et al.  Mitogen-activated protein kinase kinase-4 promotes cell survival by decreasing PTEN expression through an NF kappa B-dependent pathway. , 2007, The Journal of biological chemistry.

[62]  H. Ressom,et al.  Activation of p 53-Dependent Growth Suppression in Human Cells by Mutations in PTEN or PIK 3 CA , 2006 .

[63]  田村雅仁.  Inhibition of Cell Migration,Spreading,and Focal Adhesions by Tumor Suppressor PTEN(癌抑制遺伝子PTENによる細胞移動、伸展、接着斑の抑制) , 1999 .

[64]  Hong Sun,et al.  TEP 1 , Encoded by a Candidate Tumor Suppressor Locus , Is a Novel Protein Tyrosine Phosphatase Regulated by Transforming Growth Factor 1 @ ' , 1997 .