title: Loss of Par3 promotes breast cancer metastasis by compromising cell-cell cohesion.
abstract: The mechanisms by which tumour cells metastasize and the role that cell polarity proteins play in this process are not well understood. We report that partitioning defective protein 3 (Par3) is dysregulated in metastasis in human breast cancer, and is associated with a higher tumour grade and ErbB2-positive status. Downregulation of Par3 cooperated with ErbB2 to induce cell invasion and metastasis in vivo. Interestingly, the metastatic behaviour was not associated with an overt mesenchymal phenotype. However, loss of Par3 inhibited E-cadherin junction stability, disrupted membrane and actin dynamics at cell-cell junctions and decreased cell-cell cohesion in a manner dependent on the Tiam1/Rac-GTP pathway. Inhibition of this pathway restored E-cadherin junction stability and blocked invasive behaviour of cells lacking Par3, suggesting that loss of Par3 promotes metastatic behaviour of ErbB2-induced tumour epithelial cells by decreasing cell-cell cohesion.
authors.affiliation: Cold Spring Harbor Laboratory, New York 11724, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Xue
authors.forename: Kannan
authors.initials: K
authors.lastname: Krishnamurthy
authors.forename: D Craig
authors.initials: DC
authors.lastname: Allred
authors.forename: Senthil K
authors.initials: SK
authors.lastname: Muthuswamy
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000556:secondary; D015820:Cadherins / Q000378:metabolism; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D002450:Cell Communication; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D048430:Cell Shape; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005838:Genotype; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D007365:Intercellular Junctions / Q000378:metabolism* / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D010641:Phenotype; D034622:RNA Interference; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; D013997:Time Factors; D014162:Transfection; D014407:Tumor Cells, Cultured; D020744:rac GTP-Binding Proteins / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015820:Cadherins; D015815:Cell Adhesion Molecules; D018797:Cell Cycle Proteins; D020662:Guanine Nucleotide Exchange Factors; D008565:Membrane Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; D020744:rac GTP-Binding Proteins; C509689:PARD3 protein, human; C115084:Pard3 protein, mouse; C087334:TIAM1 protein, human; C513260:Tiam1 protein, mouse; C508053:ERBB2 protein, human; C524056:Erbb2 protein, mouse