Abstract
The progression of cancer to metastatic disease is a major cause of death. We identified miR-708 being transcriptionally repressed by polycomb repressor complex 2-induced H3K27 trimethylation in metastatic breast cancer. miR-708 targets the endoplasmic reticulum protein neuronatin to decrease intracellular calcium level, resulting in reduction of activation of ERK and FAK, decreased cell migration, and impaired metastases. Ectopic expression of neuronatin refractory to suppression by miR-708 rescued cell migration and metastasis defects. In patients with breast cancer, miR-708 expression was decreased in lymph node and distal metastases, suggesting a metastasis-suppressive role. Our findings uncover a mechanistic role for miR-708 in metastasis and provide a rationale for developing miR-708 as a therapeutic agent against metastatic breast cancer.
Copyright © 2013 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Breast Neoplasms / genetics*
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Breast Neoplasms / pathology
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Calcium / metabolism*
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Cell Movement
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Extracellular Signal-Regulated MAP Kinases / genetics
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Female
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Focal Adhesion Kinase 1 / genetics
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Focal Adhesion Kinase 1 / metabolism
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Gene Expression Regulation, Neoplastic*
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Humans
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Lung Neoplasms / genetics
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Lung Neoplasms / secondary
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MAP Kinase Signaling System / genetics
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Membrane Proteins / genetics*
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Membrane Proteins / metabolism
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Membrane Proteins / physiology
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Mice
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MicroRNAs / genetics*
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Neoplasm Metastasis / genetics*
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Nerve Tissue Proteins / genetics*
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Nerve Tissue Proteins / metabolism
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Nerve Tissue Proteins / physiology
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Polycomb-Group Proteins / physiology*
Substances
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MIRN708 microRNA, human
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Membrane Proteins
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MicroRNAs
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NNAT protein, human
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Nerve Tissue Proteins
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Polycomb-Group Proteins
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Focal Adhesion Kinase 1
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PTK2 protein, human
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Extracellular Signal-Regulated MAP Kinases
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Calcium