title: Distinct roles for paxillin and Hic-5 in regulating breast cancer cell morphology, invasion, and metastasis.
abstract: Individual metastatic tumor cells exhibit two interconvertible modes of cell motility during tissue invasion that are classified as either mesenchymal or amoeboid. The molecular mechanisms by which invasive breast cancer cells regulate this migratory plasticity have yet to be fully elucidated. Herein we show that the focal adhesion adaptor protein, paxillin , and the closely related Hic-5 have distinct and unique roles in the regulation of breast cancer cell lung metastasis by modulating cell morphology and cell invasion through three-dimensional extracellular matrices (3D ECMs). Cells depleted of paxillin by RNA interference displayed a highly elongated mesenchymal morphology, whereas Hic-5 knockdown induced an amoeboid phenotype with both cell populations exhibiting reduced plasticity, migration persistence, and velocity through 3D ECM environments. In evaluating associated signaling pathways, we determined that Rac1 activity was increased in cells devoid of paxillin whereas Hic-5 silencing resulted in elevated RhoA activity and associated Rho kinase–induced nonmuscle myosin II activity. Hic-5 was essential for adhesion formation in 3D ECMs, and analysis of adhesion dynamics and lifetime identified paxillin as a key regulator of 3D adhesion assembly, stabilization, and disassembly.
authors.affiliation: Department of Cell and Developmental Biology, State University of New York Upstate Medical University, Syracuse, NY 13210, USA.
authors.forename: Nicholas O
authors.initials: NO
authors.lastname: Deakin
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Turner
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D002417:Cattle; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D005109:Extracellular Matrix / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D060588:LIM Domain Proteins; D008175:Lung Neoplasms / Q000556:secondary; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis / Q000473:pathology*; D051419:Paxillin / Q000502:physiology*; D015398:Signal Transduction; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D060588:LIM Domain Proteins; C496061:PXN protein, human; D051419:Paxillin; C490351:TGFB1I1 protein, human; D020742:rhoA GTP-Binding Protein