Inhibition of breast cancer metastasis suppressor 1 promotes a mesenchymal phenotype in lung epithelial cells that express oncogenic K-RasV12 and loss of p53.
Expression of the breast cancer metastasis suppressor 1 (BRMS1) protein is dramatically reduced in non-small cell lung cancer (NSCLC) cells and in primary human tumors. Although BRMS1 is a known suppressor of metastasis, the mechanisms through which BRMS1 functions to regulate cell migration and invasion in response to specific NSCLC driver mutations are poorly understood. To experimentally address this, we utilized immortalized human bronchial epithelial cells in which p53 was knocked down in the presence of oncogenic K-RasV12 (HBEC3-p53KD-K-RasV12). These genetic alterations are commonly found in NSCLC and are associated with a poor prognosis. To determine the importance of BRMS1 for cytoskeletal function, cell migration and invasion in our model system we stably knocked down BRMS1. Here, we report that loss of BRMS1 in HBEC3-p53KD-K-RasV12 cells results in a dramatic increase in cell migration and invasion compared to controls that expressed BRMS1. Moreover, the loss of BRMS1 resulted in additional morphological changes including F-actin re-distribution, paxillin accumulation at the leading edge of the lamellapodium, and cellular shape changes resembling mesenchymal phenotypes. Importantly, re-expression of BRMS1 restores, in part, cell migration and invasion; however it does not fully reestablish the epithelial phenotype. These finding suggests that loss of BRMS1 results in a permanent, largely irreversible, mesenchymal phenotype associated with increased cell migration and invasion. Collectively, in NSCLC cells without p53 and expression of oncogenic K-Ras our study identifies BRMS1 as a key regulator required to maintain a cellular morphology and cytoskeletal architecture consistent with an epithelial phenotype.
Department of Surgery, University of Virginia, Charlottesville, Virginia, United States of America.
Emily H
EH
Hall
Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.
Yuan
Y
Liu
Department of Surgery, University of Virginia, Charlottesville, Virginia, United States of America.
Aizhen
A
Xiao
Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Virginia, United States of America.
Lisa
L
Shock
Department of Microbiology, Immunology &Cancer Biology, and Center for Cell signaling, University of Virginia, Charlottesville, Virginia, United States of America.
David L
DL
Brautigan
Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Virginia, United States of America.
Marty W
MW
Mayo
Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.
Prasad S
PS
Adusumilli
Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.
David R
DR
Jones
D008841:Actin Cytoskeleton / Q000378:metabolism; D056809:Alveolar Epithelial Cells / Q000378:metabolism*; D000818:Animals; D063646:Carcinogenesis / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement; D058750:Epithelial-Mesenchymal Transition; D055785:Gene Knockdown Techniques; D006801:Humans; D008819:Mice, Nude; D009154:Mutation; D009363:Neoplasm Proteins / Q000502:physiology*; D051419:Paxillin / Q000378:metabolism; D010641:Phenotype; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D018631:ras Proteins / Q000235:genetics* / Q000378:metabolism
C410024:BRMS1 protein, human; C117307:KRAS protein, human; D009363:Neoplasm Proteins; C496061:PXN protein, human; D051419:Paxillin; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins