emerging role of cell polarity proteins in breast cancer progression and metastasis

: Breast cancer is a heterogeneous group of diseases that frequently exhibits loss of growth control, and disrupted tissue organization and differentiation. Several recent studies indi-cate that apical–basal polarity provides a tumor-suppressive function, and that disrupting polarity proteins affects many stages of breast cancer progression from initiation through metastasis. In this review we highlight some of the recent advances in our understanding of the molecular mechanisms by which loss of apical–basal polarity deregulates apoptosis, proliferation, and promotes invasion and metastasis in breast cancer.

[1]  Pierre Gönczy,et al.  Mechanisms of spindle positioning: cortical force generators in the limelight. , 2013, Current opinion in cell biology.

[2]  J. Downward,et al.  Regulation of polarized morphogenesis by protein kinase C iota in oncogenic epithelial spheroids , 2013, Carcinogenesis.

[3]  Yonggang Zheng,et al.  Spatial Organization of Hippo Signaling at the Plasma Membrane Mediated by the Tumor Suppressor Merlin/NF2 , 2013, Cell.

[4]  D. St Johnston,et al.  Discs Large Links Spindle Orientation to Apical-Basal Polarity in Drosophila Epithelia , 2013, Current Biology.

[5]  R. Gelber,et al.  Patterns of Recurrence and outcome according to breast cancer subtypes in lymph node-negative disease: results from international breast cancer study group trials VIII and IX. , 2013, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[6]  P. Bult,et al.  Nuclear localization of the transcriptional coactivator YAP is associated with invasive lobular breast cancer , 2013, Cellular Oncology.

[7]  S. McKinney,et al.  Epithelial junctions maintain tissue architecture by directing planar spindle orientation , 2013, Nature.

[8]  Z. Shao,et al.  LKB1 Inhibits Breast Cancer Partially through Repressing the Hedgehog Signaling Pathway , 2013, PloS one.

[9]  P. Humbert,et al.  Localization, Not Important in All Tumor-Suppressing Properties: A Lesson Learnt from Scribble , 2013, Cells Tissues Organs.

[10]  G. Watanabe,et al.  Epithelial Cell Differentiation Regulated by MicroRNA-200a in Mammary Glands , 2013, PloS one.

[11]  S. Lelièvre,et al.  Polarity proteins as regulators of cell junction complexes: implications for breast cancer. , 2013, Pharmacology & therapeutics.

[12]  C. Rossé,et al.  Adenosine-binding motif mimicry and cellular effects of a thieno[2,3-d]pyrimidine-based chemical inhibitor of atypical protein kinase C isoenzymes. , 2013, The Biochemical journal.

[13]  D. Faratian,et al.  KIBRA exhibits MST-independent functional regulation of the Hippo signaling pathway in mammals , 2013, Oncogene.

[14]  A. Bosserhoff,et al.  The human Lgl polarity gene, Hugl-2, induces MET and suppresses Snail tumorigenesis , 2013, Oncogene.

[15]  B. Parvin,et al.  Breast fibroblasts modulate early dissemination, tumorigenesis, and metastasis through alteration of extracellular matrix characteristics. , 2013, Neoplasia.

[16]  Sridhar Ramaswamy,et al.  Circulating Breast Tumor Cells Exhibit Dynamic Changes in Epithelial and Mesenchymal Composition , 2013, Science.

[17]  K. Harvey,et al.  The Hippo Size Control Pathway—Ever Expanding , 2013, Science Signaling.

[18]  D. Allred,et al.  Loss of Par3 promotes breast cancer metastasis by compromising cell–cell cohesion , 2012, Nature Cell Biology.

[19]  H. Osada,et al.  Phosphorylation-dependent protein-protein interaction modules as potential molecular targets for cancer therapy. , 2012, Current drug targets.

[20]  C. Streuli,et al.  An integrin-ILK-microtubule network orients cell polarity and lumen formation in glandular epithelium , 2012, Nature Cell Biology.

[21]  J. Montalbano,et al.  Loss of the Par3 polarity protein promotes breast tumorigenesis and metastasis. , 2012, Cancer cell.

[22]  Daniela C. Zarnescu,et al.  Hugl1 and Hugl2 in Mammary Epithelial Cells: Polarity, Proliferation, and Differentiation , 2012, PloS one.

[23]  U. Tepass.  The apical polarity protein network in Drosophila epithelial cells: regulation of polarity, junctions, morphogenesis, cell growth, and survival. , 2012, Annual review of cell and developmental biology.

[24]  M. Georgescu,et al.  NHERF1/EBP50 controls lactation by establishing basal membrane polarity complexes with prolactin receptor , 2012, Cell Death and Disease.

[25]  Andrew J Ewald,et al.  ECM microenvironment regulates collective migration and local dissemination in normal and malignant mammary epithelium , 2012, Proceedings of the National Academy of Sciences.

[26]  R. Hynes,et al.  The Hippo pathway target, YAP, promotes metastasis through its TEAD-interaction domain , 2012, Proceedings of the National Academy of Sciences.

[27]  M. Ikura,et al.  The signaling adaptor GAB1 regulates cell polarity by acting as a PAR protein scaffold. , 2012, Molecular cell.

[28]  M. Daneshmand,et al.  Repression of cancer cell senescence by PKCι , 2012, Oncogene.

[29]  Kevin J. Cheung,et al.  Mammary collective cell migration involves transient loss of epithelial features and individual cell migration within the epithelium , 2012, Journal of Cell Science.

[30]  C. Scuoppo,et al.  Dysregulation of Cell Polarity Proteins Synergize with Oncogenes or the Microenvironment to Induce Invasive Behavior in Epithelial Cells , 2012, PloS one.

[31]  R. Fehon,et al.  Growth control by committee: intercellular junctions, cell polarity, and the cytoskeleton regulate Hippo signaling. , 2012, Developmental cell.

[32]  Z. Werb,et al.  Tumor suppressor function of Liver kinase B1 (Lkb1) is linked to regulation of epithelial integrity , 2012, Proceedings of the National Academy of Sciences.

[33]  S. Bicciato,et al.  The Hippo Transducer TAZ Confers Cancer Stem Cell-Related Traits on Breast Cancer Cells , 2011, Cell.

[34]  Jason I. Herschkowitz,et al.  Comparative oncogenomics identifies breast tumors enriched in functional tumor-initiating cells , 2011, Proceedings of the National Academy of Sciences.

[35]  M. Sajan,et al.  A novel PKC-ι inhibitor abrogates cell proliferation and induces apoptosis in neuroblastoma. , 2011, The international journal of biochemistry & cell biology.

[36]  F. Hakuno,et al.  KIBRA Suppresses Apical Exocytosis through Inhibition of aPKC Kinase Activity in Epithelial Cells , 2011, Current Biology.

[37]  A. Hall,et al.  Par6B and Atypical PKC Regulate Mitotic Spindle Orientation during Epithelial Morphogenesis* , 2011, The Journal of Biological Chemistry.

[38]  Le A. Trinh,et al.  Zebrafish Neural Tube Morphogenesis Requires Scribble-Dependent Oriented Cell Divisions , 2011, Current Biology.

[39]  D. Sgroi,et al.  The molecular pathology of breast cancer progression , 2011, The Journal of pathology.

[40]  Janet Rossant,et al.  The Crumbs complex couples cell density sensing to Hippo-dependent control of the TGF-β-SMAD pathway. , 2010, Developmental cell.

[41]  Juergen A. Knoblich,et al.  Asymmetric cell division: recent developments and their implications for tumour biology , 2010, Nature Reviews Molecular Cell Biology.

[42]  V. Band,et al.  Histological, molecular and functional subtypes of breast cancers , 2010, Cancer biology & therapy.

[43]  J. Shabanowitz,et al.  Par3 Controls Epithelial Spindle Orientation by aPKC-Mediated Phosphorylation of Apical Pins , 2010, Current Biology.

[44]  G. Longmore,et al.  Context-dependent compensatory proliferation in epithelial homeostasis and tumorigenesis , 2010, Cell cycle.

[45]  Jason I. Herschkowitz,et al.  Phenotypic and molecular characterization of the claudin-low intrinsic subtype of breast cancer , 2010, Breast Cancer Research.

[46]  Simone Brabletz,et al.  The ZEB/miR‐200 feedback loop—a motor of cellular plasticity in development and cancer? , 2010, EMBO reports.

[47]  Ian O Ellis,et al.  Intraductal proliferative lesions of the breast: morphology, associated risk and molecular biology , 2010, Modern Pathology.

[48]  W. Muller,et al.  A novel role for 14-3-3sigma in regulating epithelial cell polarity. , 2010, Genes & development.

[49]  K. Kaibuchi,et al.  Identification of focal adhesion kinase (FAK) and phosphatidylinositol 3‐kinase (PI3‐kinase) as Par3 partners by proteomic analysis , 2010, Cytoskeleton.

[50]  G. Longmore,et al.  The Cdc42/Par6/aPKC Polarity Complex Regulates Apoptosis-Induced Compensatory Proliferation in Epithelia , 2010, Current Biology.

[51]  D. Siderovski,et al.  LGN regulates mitotic spindle orientation during epithelial morphogenesis , 2010, The Journal of cell biology.

[52]  M. Rivera,et al.  A genome-wide screen for microdeletions reveals disruption of polarity complex genes in diverse human cancers. , 2010, Cancer research.

[53]  Robert L Sutherland,et al.  PI3K pathway activation in breast cancer is associated with the basal‐like phenotype and cancer‐specific mortality , 2010, International journal of cancer.

[54]  W. Deng,et al.  Kibra functions as a tumor suppressor protein that regulates Hippo signaling in conjunction with Merlin and Expanded. , 2010, Developmental cell.

[55]  P. Friedl,et al.  The Journal of Cell Biology , 2002 .

[56]  R. Huang,et al.  Epithelial-Mesenchymal Transitions in Development and Disease , 2009, Cell.

[57]  J. Visvader,et al.  Keeping abreast of the mammary epithelial hierarchy and breast tumorigenesis. , 2009, Genes & development.

[58]  Pier Paolo Di Fiore,et al.  The Tumor Suppressor p53 Regulates Polarity of Self-Renewing Divisions in Mammary Stem Cells , 2009, Cell.

[59]  C. Doe,et al.  Identification of an Aurora-A/PinsLINKER/ Dlg Spindle Orientation Pathway using Induced Cell Polarity in S2 Cells , 2009, Cell.

[60]  R. Shaw,et al.  The LKB1–AMPK pathway: metabolism and growth control in tumour suppression , 2009, Nature Reviews Cancer.

[61]  I. Macara,et al.  The Par3/aPKC interaction is essential for end bud remodeling and progenitor differentiation during mammary gland morphogenesis. , 2009, Genes & development.

[62]  W. Hong,et al.  TEADs Mediate Nuclear Retention of TAZ to Promote Oncogenic Transformation* , 2009, Journal of Biological Chemistry.

[63]  Nicholas J. Wang,et al.  Characterization of a naturally occurring breast cancer subset enriched in epithelial-to-mesenchymal transition and stem cell characteristics. , 2009, Cancer research.

[64]  P. Pandolfi,et al.  PML, YAP, and p73 are components of a proapoptotic autoregulatory feedback loop. , 2008, Molecular cell.

[65]  Z. Xuan,et al.  Deregulation of Scribble Promotes Mammary Tumorigenesis and Reveals a Role for Cell Polarity in Carcinoma , 2008, Cell.

[66]  A. Hall,et al.  Cdc42 controls spindle orientation to position the apical surface during epithelial morphogenesis , 2008, The Journal of cell biology.

[67]  E. Montgomery,et al.  Expression of Yes-associated protein in common solid tumors. , 2008, Human pathology.

[68]  Marissa E. Nolan,et al.  The polarity protein Par6 induces cell proliferation and is overexpressed in breast cancer. , 2008, Cancer research.

[69]  Harold Varmus,et al.  Seeding and Propagation of Untransformed Mouse Mammary Cells in the Lung , 2008, Science.

[70]  Hao Wu,et al.  Par-3-mediated Junctional Localization of the Lipid Phosphatase PTEN Is Required for Cell Polarity Establishment* , 2008, Journal of Biological Chemistry.

[71]  Jiandie D. Lin,et al.  TEAD mediates YAP-dependent gene induction and growth control. , 2008, Genes & development.

[72]  C. Mein,et al.  Yes-associated protein (YAP) functions as a tumor suppressor in breast , 2008, Cell Death and Differentiation.

[73]  T. Ishikawa,et al.  The overexpression and altered localization of the atypical protein kinase C lambda/iota in breast cancer correlates with the pathologic type of these tumors. , 2008, Human pathology.

[74]  J. Thiery,et al.  β1 Integrin deletion from the basal compartment of the mammary epithelium affects stem cells , 2008, Nature Cell Biology.

[75]  Wenjun Guo,et al.  The Epithelial-Mesenchymal Transition Generates Cells with Properties of Stem Cells , 2008, Cell.

[76]  G. Goodall,et al.  The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1 , 2008, Nature Cell Biology.

[77]  Andrew J Ewald,et al.  Collective epithelial migration and cell rearrangements drive mammary branching morphogenesis. , 2008, Developmental cell.

[78]  Q. Zhan,et al.  Amplification of PRKCI, located in 3q26, is associated with lymph node metastasis in esophageal squamous cell carcinoma , 2008, Genes, chromosomes & cancer.

[79]  A. Dimmler,et al.  The transcriptional repressor ZEB1 promotes metastasis and loss of cell polarity in cancer. , 2008, Cancer research.

[80]  R. Foisner,et al.  The transcription factor ZEB1 (δEF1) promotes tumour cell dedifferentiation by repressing master regulators of epithelial polarity , 2007, Oncogene.

[81]  Jun Hee Lee,et al.  Energy-dependent regulation of cell structure by AMP-activated protein kinase , 2007, Nature.

[82]  G. Zografos,et al.  Precursors and preinvasive lesions of the breast: the role of molecular prognostic markers in the diagnostic and therapeutic dilemma , 2007, World journal of surgical oncology.

[83]  Zhiyuan Hu,et al.  Identification of conserved gene expression features between murine mammary carcinoma models and human breast tumors , 2007, Genome Biology.

[84]  M. Caplan,et al.  AMP-activated protein kinase regulates the assembly of epithelial tight junctions , 2006, Proceedings of the National Academy of Sciences.

[85]  Marissa E. Nolan,et al.  Par6–aPKC uncouples ErbB2 induced disruption of polarized epithelial organization from proliferation control , 2006, Nature Cell Biology.

[86]  A. Fields,et al.  Aurothiomalate Inhibits Transformed Growth by Targeting the PB1 Domain of Protein Kinase Cι* , 2006, Journal of Biological Chemistry.

[87]  A. Suzuki,et al.  The PAR-aPKC system: lessons in polarity , 2006, Journal of Cell Science.

[88]  B. Gumbiner,et al.  The mammalian Scribble polarity protein regulates epithelial cell adhesion and migration through E-cadherin , 2005, The Journal of cell biology.

[89]  Elaine Fuchs,et al.  Asymmetric cell divisions promote stratification and differentiation of mammalian skin , 2005, Nature.

[90]  J. Copland,et al.  Atypical Protein Kinase Cι Plays a Critical Role in Human Lung Cancer Cell Growth and Tumorigenicity* , 2005, Journal of Biological Chemistry.

[91]  Gordon B Mills,et al.  Atypical PKCiota contributes to poor prognosis through loss of apical-basal polarity and cyclin E overexpression in ovarian cancer. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[92]  B. Margolis,et al.  Multiple regions of Crumbs3 are required for tight junction formation in MCF10A cells , 2005, Journal of Cell Science.

[93]  D. Birnbaum,et al.  Junctional recruitment of mammalian Scribble relies on E-cadherin engagement , 2005, Oncogene.

[94]  V. Vasioukhin.  Faculty Opinions recommendation of Regulation of the polarity protein Par6 by TGFbeta receptors controls epithelial cell plasticity. , 2005 .

[95]  I. Macara,et al.  Mammalian Pins Is a Conformational Switch that Links NuMA to Heterotrimeric G Proteins , 2004, Cell.

[96]  A. Bilancio,et al.  Role of Atypical Protein Kinase C in Estradiol-Triggered G1/S Progression of MCF-7 Cells , 2004, Molecular and Cellular Biology.

[97]  A. Suzuki,et al.  aPKC Acts Upstream of PAR-1b in Both the Establishment and Maintenance of Mammalian Epithelial Polarity , 2004, Current Biology.

[98]  T. Hurd,et al.  Tight Junction Protein Par6 Interacts with an Evolutionarily Conserved Region in the Amino Terminus of PALS1/Stardust* , 2004, Journal of Biological Chemistry.

[99]  Jérôme Boudeau,et al.  LKB1 is a master kinase that activates 13 kinases of the AMPK subfamily, including MARK/PAR‐1 , 2004, The EMBO journal.

[100]  A. Elias,et al.  Multistep tumorigenesis and the microenvironment , 2004, Breast Cancer Research.

[101]  S. Goodison,et al.  Prolonged dormancy and site-specific growth potential of cancer cells spontaneously disseminated from nonmetastatic breast tumors as revealed by labeling with green fluorescent protein. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[102]  S. Schnitt.  The diagnosis and management of pre-invasive breast disease: Flat epithelial atypia – classification, pathologic features and clinical significance , 2003, Breast Cancer Research.

[103]  S. Morrison,et al.  Prospective identification of tumorigenic breast cancer cells , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[104]  T. Hurd,et al.  Direct interaction of two polarity complexes implicated in epithelial tight junction assembly , 2003, Nature Cell Biology.

[105]  Sophie Lelièvre,et al.  beta4 integrin-dependent formation of polarized three-dimensional architecture confers resistance to apoptosis in normal and malignant mammary epithelium. , 2002, Cancer cell.

[106]  D. Vestweber,et al.  The cell polarity protein ASIP/PAR‐3 directly associates with junctional adhesion molecule (JAM) , 2001, The EMBO journal.

[107]  D Bilder,et al.  Cooperative regulation of cell polarity and growth by Drosophila tumor suppressors. , 2000, Science.

[108]  N. Perrimon,et al.  Localization of apical epithelial determinants by the basolateral PDZ protein Scribble , 2000, Nature.

[109]  D. Morton,et al.  Identification of genes required for cytoplasmic localization in early C. elegans embryos , 1988, Cell.

[110]  Steven J. M. Jones,et al.  Comprehensive molecular portraits of human breast tumours , 2013 .

[111]  P. Meltzer,et al.  PAR6B is required for tight junction formation and activated PKCζ localization in breast cancer. , 2012, American journal of cancer research.

[112]  W. Muller,et al.  Loss of the 14-3-3σ tumor suppressor is a critical event in ErbB2-mediated tumor progression. , 2012, Cancer discovery.

[113]  Yu Zhou,et al.  MPP3 inactivation by promoter CpG islands hypermethylation in colorectal carcinogenesis. , 2012, Cancer biomarkers : section A of Disease markers.

[114]  S. Alahari,et al.  Breast cancer stem cells: a new challenge for breast cancer treatment. , 2011, Frontiers in bioscience.

[115]  John G. Collard,et al.  Tiam1-deficiency impairs mammary tumor formation in MMTV-c-neu but not in MMTV-c-myc mice , 2008, Journal of Cancer Research and Clinical Oncology.

[116]  X. Ying,et al.  aPKC inhibitors might be the sensitizer of chemotherapy and adoptive immunotherapy in the treatment of hASIPa-overexpressed breast cancer. , 2008, Oncology research.

[117]  M. J. van de Vijver.  Biological variables and prognosis of DCIS. , 2005, Breast.