title: PRL-3 engages the focal adhesion pathway in triple-negative breast cancer cells to alter actin structure and substrate adhesion properties critical for cell migration and invasion.
abstract: Triple-negative breast cancers (TNBCs) are among the most aggressive cancers characterized by a high propensity to invade, metastasize and relapse. We previously reported that the TNBC-specific inhibitor, AMPI-109, significantly impairs the ability of TNBC cells to migrate and invade by reducing levels of the metastasis-promoting phosphatase, PRL-3. Here, we examined the mechanisms by which AMPI-109 and loss of PRL-3 impede cell migration and invasion. AMPI-109 treatment or knock down of PRL-3 expression were associated with deactivation of Src and ERK signaling and concomitant downregulation of RhoA and Rac1/2/3 GTPase protein levels. These cellular changes led to rearranged filamentous actin networks necessary for cell migration and invasion. Conversely, overexpression of PRL-3 promoted TNBC cell invasion by upregulating matrix metalloproteinase 10, which resulted in increased TNBC cell adherence to, and degradation of, the major basement membrane component laminin. Our data demonstrate that PRL-3 engages the focal adhesion pathway in TNBC cells as a key mechanism for promoting TNBC cell migration and invasion. Collectively, these data suggest that blocking PRL-3 activity may be an effective method for reducing the metastatic potential of TNBC cells.
authors.affiliation: Department of Pathology, University of Colorado School of Medicine, Aurora, CO, USA.
authors.forename: Hamid H
authors.initials: HH
authors.lastname: Gari
authors.affiliation: Department of Pathology, University of Colorado School of Medicine, Aurora, CO, USA.
authors.forename: Gregory D
authors.initials: GD
authors.lastname: DeGala
authors.affiliation: Department of Medicine, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Rahul
authors.initials: R
authors.lastname: Ray
authors.affiliation: Department of Pathology, University of Colorado School of Medicine, Aurora, CO, USA.
authors.forename: M Scott
authors.initials: MS
authors.lastname: Lucia
authors.affiliation: Department of Pathology, University of Colorado School of Medicine, Aurora, CO, USA. Electronic address: Jim.Lambert@ucdenver.edu.
authors.forename: James R
authors.initials: JR
authors.lastname: Lambert
mesh_terms: D008841:Actin Cytoskeleton / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D000970:Antineoplastic Agents / Q000494:pharmacology; D002117:Calcitriol / Q000031:analogs & derivatives / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D022001:Focal Adhesions / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D006801:Humans; D007797:Laminin / Q000378:metabolism; D053506:Matrix Metalloproteinase 10 / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D020744:rac GTP-Binding Proteins / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: C104313:1,25-dihydroxyvitamin D3-3-bromoacetate; D000970:Antineoplastic Agents; D007797:Laminin; D009363:Neoplasm Proteins; C066737:RHOA protein, human; D019061:src-Family Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; C484730:PTP4A3 protein, human; D017027:Protein Tyrosine Phosphatases; C511770:MMP10 protein, human; D053506:Matrix Metalloproteinase 10; D020744:rac GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein; D002117:Calcitriol
keywords: Laminin; MMP; Metastasis; PRL-3; Triple-negative breast cancer