title: Snail promotes epithelial mesenchymal transition in breast cancer cells in part via activation of nuclear ERK2.
abstract: Snail transcription factor is up-regulated in several cancers and associated with increased tumor migration and invasion via induction of epithelial-to-mesenchymal transition (EMT). MAPK (ERK1/2) signaling regulates cellular processes including cell motility, adhesion, and invasion. We investigated the regulation of ERK1/2 by Snail in breast cancer cells. ERK1/2 activity (p-ERK) was higher in breast cancer patient tissue as compared to normal tissue. Snail and p-ERK were increased in several breast cancer cell lines as compared to normal mammary epithelial cells. Snail knockdown in MDA-MB-231 and T47-D breast cancer cells decreased or re-localized p-ERK from the nuclear compartment to the cytoplasm. Snail overexpression in MCF-7 breast cancer cells induced EMT, increased cell migration, decreased cell adhesion and also increased tumorigenicity. Snail induced nuclear translocation of p-ERK, and the activation of its subcellular downstream effector, Elk-1. Inhibiting MAPK activity with UO126 or knockdown of ERK2 isoform with siRNA in MCF-7 Snail cells reverted EMT induced by Snail as shown by decreased Snail and vimentin expression, decreased cell migration and increased cell adhesion. Overall, our data suggest that ERK2 isoform activation by Snail in aggressive breast cancer cells leads to EMT associated with increased cell migration and decreased cell adhesion. This regulation is enhanced by positive feedback regulation of Snail by ERK2. Therefore, therapeutic targeting of ERK2 isoform may be beneficial for breast cancer.
authors.affiliation: Center for Cancer Research and Therapeutic Development and Department of Biological Sciences, Clark Atlanta University, Atlanta, Georgia, United States of America.
authors.forename: Bethany N
authors.initials: BN
authors.lastname: Smith
authors.affiliation: Center for Cancer Research and Therapeutic Development and Department of Biological Sciences, Clark Atlanta University, Atlanta, Georgia, United States of America.
authors.forename: Liza J
authors.initials: LJ
authors.lastname: Burton
authors.affiliation: Center for Cancer Research and Therapeutic Development and Department of Biological Sciences, Clark Atlanta University, Atlanta, Georgia, United States of America.
authors.forename: Veronica
authors.initials: V
authors.lastname: Henderson
authors.affiliation: Center for Cancer Research and Therapeutic Development and Department of Biological Sciences, Clark Atlanta University, Atlanta, Georgia, United States of America.
authors.forename: Diandra D
authors.initials: DD
authors.lastname: Randle
authors.affiliation: Center for Cancer Research and Therapeutic Development and Department of Biological Sciences, Clark Atlanta University, Atlanta, Georgia, United States of America.
authors.forename: Derrick J
authors.initials: DJ
authors.lastname: Morton
authors.affiliation: Center for Cancer Research and Therapeutic Development and Department of Biological Sciences, Clark Atlanta University, Atlanta, Georgia, United States of America.
authors.forename: Basil A
authors.initials: BA
authors.lastname: Smith
authors.affiliation: The Department of Hematology and Medical Oncology and Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Latonia
authors.initials: L
authors.lastname: Taliaferro-Smith
authors.affiliation: Center for Cancer Research and Therapeutic Development and Department of Biological Sciences, Clark Atlanta University, Atlanta, Georgia, United States of America.
authors.forename: Peri
authors.initials: P
authors.lastname: Nagappan
authors.affiliation: Department of Biology, Tuskegee University, Tuskegee, Alabama, United States of America.
authors.forename: Clayton
authors.initials: C
authors.lastname: Yates
authors.affiliation: The Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Majd
authors.initials: M
authors.lastname: Zayzafoon
authors.affiliation: The Uro-Oncology Research Program, Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.
authors.forename: Leland W K
authors.initials: LW
authors.lastname: Chung
authors.affiliation: Center for Cancer Research and Therapeutic Development and Department of Biological Sciences, Clark Atlanta University, Atlanta, Georgia, United States of America.
authors.forename: Valerie A
authors.initials: VA
authors.lastname: Odero-Marah
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D002467:Cell Nucleus / Q000201:enzymology*; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008819:Mice, Nude; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D021381:Protein Transport; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000502:physiology*
chemical_list: D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D046988:Proteasome Endopeptidase Complex