title: Dysregulation of cell polarity proteins synergize with oncogenes or the microenvironment to induce invasive behavior in epithelial cells.
abstract: Changes in expression and localization of proteins that regulate cell and tissue polarity are frequently observed in carcinoma. However, the mechanisms by which changes in cell polarity proteins regulate carcinoma progression are not well understood. Here, we report that loss of polarity protein expression in epithelial cells primes them for cooperation with oncogenes or changes in tissue microenvironment to promote invasive behavior. Activation of ErbB2 in cells lacking the polarity regulators Scribble, Dlg1 or AF-6, induced invasive properties. This cooperation required the ability of ErbB2 to regulate the Par6/aPKC polarity complex. Inhibition of the ErbB2-Par6 pathway was sufficient to block ErbB2-induced invasion suggesting that two polarity hits may be needed for ErbB2 to promote invasion. Interestingly, in the absence of ErbB2 activation, either a combined loss of two polarity proteins, or exposure of cells lacking one polarity protein to cytokines IL-6 or TNFα induced invasive behavior in epithelial cells. We observed the invasive behavior only when cells were plated on a stiff matrix (Matrigel/Collagen-1) and not when plated on a soft matrix (Matrigel alone). Cells lacking two polarity proteins upregulated expression of EGFR and activated Akt. Inhibition of Akt activity blocked the invasive behavior identifying a mechanism by which loss of polarity promotes invasion of epithelial cells. Thus, we demonstrate that loss of polarity proteins confers phenotypic plasticity to epithelial cells such that they display normal behavior under normal culture conditions but display aggressive behavior in response to activation of oncogenes or exposure to cytokines.
authors.affiliation: Ontario Cancer Institute, Campbell Family Institute for Breast Cancer Research, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Samit
authors.initials: S
authors.lastname: Chatterjee
authors.forename: Laurie
authors.initials: L
authors.lastname: Seifried
authors.forename: Michael E
authors.initials: ME
authors.lastname: Feigin
authors.forename: Don L
authors.initials: DL
authors.lastname: Gibbons
authors.forename: Claudio
authors.initials: C
authors.lastname: Scuoppo
authors.forename: Wei
authors.initials: W
authors.lastname: Lin
authors.forename: Zain H
authors.initials: ZH
authors.lastname: Rizvi
authors.forename: Evan
authors.initials: E
authors.lastname: Lind
authors.forename: Dilan
authors.initials: D
authors.lastname: Dissanayake
authors.forename: Jonathan
authors.initials: J
authors.lastname: Kurie
authors.forename: Pam
authors.initials: P
authors.lastname: Ohashi
authors.forename: Senthil K
authors.initials: SK
authors.lastname: Muthuswamy
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D002465:Cell Movement / Q000235:genetics; D016764:Cell Polarity / Q000235:genetics; D060833:Cellular Microenvironment; D016207:Cytokines / Q000378:metabolism; D000074288:Discs Large Homolog 1 Protein; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D005786:Gene Expression Regulation; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D016547:Kinesins / Q000235:genetics / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D057507:Mice, 129 Strain; D009218:Myosins / Q000235:genetics / Q000378:metabolism; D009857:Oncogenes; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016207:Cytokines; D000074288:Discs Large Homolog 1 Protein; D066246:ErbB Receptors; D018836:Inflammation Mediators; D016547:Kinesins; D008565:Membrane Proteins; D009218:Myosins; D051057:Proto-Oncogene Proteins c-akt; D018719:Erb-b2 Receptor Tyrosine Kinases; C095516:AFDN protein, human; C513314:DLG1 protein, human