The phosphatidyl inositol 3-kinase signaling network: implications for human breast cancer

The phosphatidyl inositol 3-kinase (PI3K)/Akt pathway is activated downstream of a variety of extracellular signals and activation of this signaling pathway impacts a number of cellular processes including cell growth, proliferation and survival. The alteration of components of this pathway, through either activation of oncogenes or inactivation of tumor suppressors, disrupts a signaling equilibrium and can thus lead to cellular transformation. The frequent dysregulation of the PI3K/Akt pathway in human cancer has made components of this pathway attractive for therapeutic targeting; however, a more comprehensive understanding of the signaling intricacies is necessary to develop pharmacological agents to target not only specific molecules, but also specific functions. Here, we review a series of experiments examining the contribution of molecules of this signaling network including PI3K, phosphatase and tensin homolog deleted on chromosome 10, integrin-linked kinase and Akt and address the significance to human breast cancer.

[1]  M. Roussel,et al.  Glycogen synthase kinase-3beta regulates cyclin D1 proteolysis and subcellular localization. , 1998, Genes & development.

[2]  R. Cardiff,et al.  Mammary epithelial-specific expression of the integrin linked kinase (ILK) results in the induction of mammary gland hyperplasias and tumors in transgenic mice , 2001, Oncogene.

[3]  S. Dedhar,et al.  The integrin-linked kinase (ILK) suppresses anoikis , 2000, Oncogene.

[4]  J. Frahm,et al.  Essential role of protein kinase Bγ (PKBγ/Akt3) in postnatal brain development but not in glucose homeostasis , 2005, Development.

[5]  D. Huntsman,et al.  Increased expression of integrin-linked kinase is correlated with melanoma progression and poor patient survival. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[6]  R. Fässler,et al.  The integrin–actin connection, an eternal love affair , 2003, The EMBO journal.

[7]  C. Wu.  ILK interactions. , 2001, Journal of Cell Science.

[8]  Mammary gland involution is delayed by activated Akt in transgenic mice. , 2001, Molecular endocrinology.

[9]  P. Edwards,et al.  Integrin-linked kinase regulates phosphorylation of serine 473 of protein kinase B by an indirect mechanism , 1999, Oncogene.

[10]  M. Kook,et al.  ILK (β1-integrin-linked protein kinase): a novel immunohistochemical marker for Ewing’s sarcoma and primitive neuroectodermal tumour , 1998, Virchows Archiv.

[11]  D. Guertin,et al.  Phosphorylation and Regulation of Akt/PKB by the Rictor-mTOR Complex , 2005, Science.

[12]  B. Karlan,et al.  Overexpression of AKT2/protein kinase Bbeta leads to up-regulation of beta1 integrins, increased invasion, and metastasis of human breast and ovarian cancer cells. , 2003, Cancer research.

[13]  J. McManaman,et al.  Expression of constitutively activated Akt in the mammary gland leads to excess lipid synthesis during pregnancy and lactation Published, JLR Papers in Press, April 16, 2003. DOI 10.1194/jlr.M300045-JLR200 , 2003, Journal of Lipid Research.

[14]  C. G. Zervas,et al.  Integrin Adhesion: When Is a Kinase a Kinase? , 2002, Current Biology.

[15]  T. Ludwig,et al.  Role for Akt3/protein kinase Bgamma in attainment of normal brain size. , 2005, Molecular and cellular biology.

[16]  C. G. Zervas,et al.  Drosophila Integrin-Linked Kinase Is Required at Sites of Integrin Adhesion to Link the Cytoskeleton to the Plasma Membrane , 2001, The Journal of cell biology.

[17]  Mariano Provencio,et al.  Allelic loss of the PTEN region (10q23) in breast carcinomas of poor pathophenotype , 1999, Breast Cancer Research and Treatment.

[18]  S. Dedhar,et al.  Inhibition of ILK in PTEN-mutant human glioblastomas inhibits PKB/Akt activation, induces apoptosis, and delays tumor growth , 2005, Oncogene.

[19]  K. Kaestner,et al.  Insulin Resistance and a Diabetes Mellitus-Like Syndrome in Mice Lacking the Protein Kinase Akt2 (PKBβ) , 2001 .

[20]  Yun Hua,et al.  A New Focal Adhesion Protein That Interacts with Integrin-Linked Kinase and Regulates Cell Adhesion and Spreading , 2001, The Journal of cell biology.

[21]  M. Gleave,et al.  Regulation of tumor angiogenesis by integrin-linked kinase (ILK). , 2004, Cancer cell.

[22]  C. Riley,et al.  Integrin‐linked kinase expression increases with ovarian tumour grade and is sustained by peritoneal tumour fluid , 2003, The Journal of pathology.

[23]  J. Romashkova,et al.  NF-κB is a target of AKT in anti-apoptotic PDGF signalling , 1999, Nature.

[24]  H. Varmus,et al.  Deficiency of Pten accelerates mammary oncogenesis in MMTV-Wnt-1 transgenic mice , 2001, BMC Molecular Biology.

[25]  S. Dedhar,et al.  Inhibition of integrin-linked kinase (ILK) suppresses activation of protein kinase B/Akt and induces cell cycle arrest and apoptosis of PTEN-mutant prostate cancer cells. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[26]  R. Cardiff,et al.  Activation of Akt (Protein Kinase B) in Mammary Epithelium Provides a Critical Cell Survival Signal Required for Tumor Progression , 2001, Molecular and Cellular Biology.

[27]  L. Donehower,et al.  The Integrin-linked Kinase Regulates the Cyclin D1 Gene through Glycogen Synthase Kinase 3β and cAMP-responsive Element-binding Protein-dependent Pathways* , 2000, The Journal of Biological Chemistry.

[28]  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.

[29]  J. Woodgett,et al.  Phosphoinositide-3-OH kinase-dependent regulation of glycogen synthase kinase 3 and protein kinase B/AKT by the integrin-linked kinase. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[30]  W. El-Deiry.  Akt takes centre stage in cell-cycle deregulation , 2001, Nature Cell Biology.

[31]  松尾 洋一,et al.  2124 膵癌の転移・浸潤能に関するIntegrin-linked kinaseの関与(膵基礎2,一般演題,第61回日本消化器外科学会定期学術総会) , 2006 .

[32]  P. Dennis,et al.  Activation of the PI3K/Akt pathway and chemotherapeutic resistance. , 2002, Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy.

[33]  Yiling Lu,et al.  Exploiting the PI3K/AKT Pathway for Cancer Drug Discovery , 2005, Nature Reviews Drug Discovery.

[34]  K. Inoki,et al.  TSC2: filling the GAP in the mTOR signaling pathway. , 2004, Trends in biochemical sciences.

[35]  J. Cheng,et al.  Molecular alterations of the AKT2 oncogene in ovarian and breast carcinomas , 1995, International journal of cancer.

[36]  Alfonso Bellacosa,et al.  Cytoplasmic relocalization and inhibition of the cyclin-dependent kinase inhibitor p27Kip1 by PKB/Akt-mediated phosphorylation in breast cancer , 2002, Nature Medicine.

[37]  J. Deddens,et al.  Integrin-linked kinase expression increases with prostate tumor grade. , 2001, Clinical cancer research : an official journal of the American Association for Cancer Research.

[38]  S. Dedhar,et al.  Integrin-linked Protein Kinase Regulates Fibronectin Matrix Assembly, E-cadherin Expression, and Tumorigenicity* , 1998, The Journal of Biological Chemistry.

[39]  Hiroyuki Konishi,et al.  The PIK3CA gene is mutated with high frequency in human breast cancers , 2004, Cancer biology & therapy.

[40]  S. R. Datta,et al.  Akt Phosphorylation of BAD Couples Survival Signals to the Cell-Intrinsic Death Machinery , 1997, Cell.

[41]  J. Brugge,et al.  Distinct roles of Akt1 and Akt2 in regulating cell migration and epithelial–mesenchymal transition , 2005, The Journal of cell biology.

[42]  W. Liu,et al.  Up-regulation of Akt3 in Estrogen Receptor-deficient Breast Cancers and Androgen-independent Prostate Cancer Lines* , 1999, The Journal of Biological Chemistry.

[43]  Hanina Hibshoosh,et al.  PIK3CA mutations correlate with hormone receptors, node metastasis, and ERBB2, and are mutually exclusive with PTEN loss in human breast carcinoma. , 2005, Cancer research.

[44]  R. Glazer,et al.  Delayed mammary gland involution in MMTV-AKT1 transgenic mice , 2002, Oncogene.

[45]  D. Rawlings,et al.  Protein Kinase C βII Regulates Akt Phosphorylation on Ser-473 in a Cell Type- and Stimulus-specific Fashion*♦ , 2004, Journal of Biological Chemistry.

[46]  J. Boyd,et al.  Mutation analysis of the putative tumor suppressor gene PTEN/MMAC1 in primary breast carcinomas. , 1997, Cancer research.

[47]  P. Vogt,et al.  Phosphatidylinositol 3-kinase mutations identified in human cancer are oncogenic. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[48]  Olle Stål,et al.  Akt kinases in breast cancer and the results of adjuvant therapy , 2003, Breast Cancer Research.

[49]  C. Larsson,et al.  Somatic deletions and mutations in the Cowden disease gene, PTEN, in sporadic thyroid tumors. , 1997, Cancer research.

[50]  I. Roninson,et al.  Growth retardation and increased apoptosis in mice with homozygous disruption of the Akt1 gene. , 2001, Genes & development.

[51]  A. Weiss,et al.  Induction of NF-kappaB by the Akt/PKB kinase. , 1999, Current biology : CB.

[52]  D. Vertommen,et al.  Phosphorylation and Activation of Heart 6-Phosphofructo-2-kinase by Protein Kinase B and Other Protein Kinases of the Insulin Signaling Cascades* , 1997, The Journal of Biological Chemistry.

[53]  S. Dedhar,et al.  Regulation of Protein Kinase B/Akt-Serine 473 Phosphorylation by Integrin-linked Kinase , 2001, The Journal of Biological Chemistry.

[54]  G. Mills,et al.  MMAC1/PTEN mutations in primary tumor specimens and tumor cell lines. , 1997, Cancer research.

[55]  M. Greenberg,et al.  Akt Promotes Cell Survival by Phosphorylating and Inhibiting a Forkhead Transcription Factor , 1999, Cell.

[56]  D. Hanahan,et al.  The Hallmarks of Cancer , 2000, Cell.

[57]  A. Toker,et al.  Akt blocks breast cancer cell motility and invasion through the transcription factor NFAT. , 2005, Molecular cell.

[58]  Alfonso Bellacosa,et al.  Epithelial–mesenchymal transition in development and cancer: role of phosphatidylinositol 3′ kinase/AKT pathways , 2005, Oncogene.

[59]  Michihiko Yoshida,et al.  A Novel Integrin-Linked Kinase–Binding Protein, Affixin, Is Involved in the Early Stage of Cell–Substrate Interaction , 2001, The Journal of cell biology.

[60]  Shunyou Wang,et al.  Pten deletion leads to the expansion of a prostatic stem/progenitor cell subpopulation and tumor initiation , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[61]  J. Varakis,et al.  ILK over‐expression in human colon cancer progression correlates with activation of β‐catenin, down‐regulation of E‐cadherin and activation of the Akt–FKHR pathway , 2006, The Journal of pathology.

[62]  G. Mills,et al.  Targeting integrin-linked kinase inhibits Akt signaling pathways and decreases tumor progression of human glioblastoma , 2005, Molecular Cancer Therapeutics.

[63]  D. Moerman,et al.  C. elegans PAT-4/ILK Functions as an Adaptor Protein within Integrin Adhesion Complexes , 2002, Current Biology.

[64]  T. Mak,et al.  High incidence of breast and endometrial neoplasia resembling human Cowden syndrome in pten+/- mice. , 2000, Cancer research.

[65]  Robert D Cardiff,et al.  Activation of Akt-1 (PKB-alpha) can accelerate ErbB-2-mediated mammary tumorigenesis but suppresses tumor invasion. , 2004, Cancer research.

[66]  J. Ptak,et al.  High Frequency of Mutations of the PIK3CA Gene in Human Cancers , 2004, Science.

[67]  G. Mills,et al.  Integrin-linked kinase is a potential therapeutic target for anaplastic thyroid cancer , 2005, Molecular Cancer Therapeutics.

[68]  L. Peso,et al.  Interleukin-3-induced phosphorylation of BAD through the protein kinase Akt. , 1997, Science.

[69]  L. Pfeffer,et al.  NF-κB activation by tumour necrosis factor requires the Akt serine–threonine kinase , 1999, Nature.

[70]  M. Nelen,et al.  Germline mutations in the PTEN/MMAC1 gene in patients with Cowden disease. , 1997, Human molecular genetics.

[71]  M. Birnbaum,et al.  Akt1/PKBα Is Required for Normal Growth but Dispensable for Maintenance of Glucose Homeostasis in Mice* , 2001, The Journal of Biological Chemistry.

[72]  S. Dedhar,et al.  Dysregulation of integrin-linked kinase (ILK) signaling in colonic polyposis , 2001, Oncogene.

[73]  M. Birnbaum,et al.  Expression of a Constitutively Active Akt Ser/Thr Kinase in 3T3-L1 Adipocytes Stimulates Glucose Uptake and Glucose Transporter 4 Translocation* , 1996, The Journal of Biological Chemistry.

[74]  J E Paciga,et al.  AKT1/PKBalpha kinase is frequently elevated in human cancers and its constitutive activation is required for oncogenic transformation in NIH3T3 cells. , 2001, The American journal of pathology.

[75]  Y. Nakamura,et al.  Somatic mutation of the PTEN/MMAC1 gene in breast cancers with microsatellite instability. , 1999, Cancer Letters.

[76]  F. Kikkawa,et al.  Fibronectin activates matrix metalloproteinase-9 secretion via the MEK1-MAPK and the PI3K-Akt pathways in ovarian cancer cells , 2004, Clinical & Experimental Metastasis.

[77]  S. Dedhar,et al.  Regulation of cell adhesion and anchorage-dependent growth by a new β1-integrin-linked protein kinase , 1996, Nature.

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

[79]  A. Newton,et al.  Akt/Protein Kinase B Is Regulated by Autophosphorylation at the Hypothetical PDK-2 Site* , 2000, The Journal of Biological Chemistry.

[80]  P. Cohen,et al.  Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B , 1995, Nature.

[81]  M. Hung,et al.  Cytoplasmic localization of p21Cip1/WAF1 by Akt-induced phosphorylation in HER-2/neu-overexpressing cells , 2001, Nature Cell Biology.

[82]  L. Hennighausen,et al.  Conditional loss of PTEN leads to precocious development and neoplasia in the mammary gland. , 2002, Development.