Abstract
Dysregulation of microRNAs is a common feature in human cancers, including breast cancer (BC). Here we describe the epigenetic regulation of miR-148a and miR-152 and their impact on BC cells. Due to the hypermethylation of CpG island, the expression levels of both miR-148a and miR-152 (miR-148a/152) are decreased in BC tissues and cells. DNMT1, the DNA methyltransferase 1 for the maintenance methylation, is aberrantly up-regulated in BC and its overexpression is responsible for hypermethylation of miR-148a and miR-152 promoters. Intriguingly, we found that DNMT1 expression, which is one of the targets of miR-148a/152, is inversely correlated with the expression levels of miR-148a/152 in BC tissues. Those results lead us to propose a negative feedback regulatory loop between miR-148a/152 and DNMT1 in BC. More importantly, we demonstrate that IGF-IR and IRS1, often overexpressed in BC, are two novel targets of miR-148a/152. Overexpression of miR-148a or miR-152 significantly inhibits BC cell proliferation, colony formation, and tumor angiogenesis via targeting IGF-IR and IRS1 and suppressing their downstream AKT and MAPK/ERK signaling pathways. Our results suggest a novel miR-148a/152-DNMT1 regulatory circuit and reveal that miR-148a and miR-152 act as tumor suppressors by targeting IGF-IR and IRS1, and that restoration of miR-148a/152 expression may provide a strategy for therapeutic application to treat BC patients.
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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Adult
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Aged
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Breast Neoplasms / genetics
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Breast Neoplasms / metabolism
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Breast Neoplasms / pathology
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Cell Line, Tumor
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Cell Proliferation
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Cell Transformation, Neoplastic / genetics*
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DNA (Cytosine-5-)-Methyltransferase 1
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DNA (Cytosine-5-)-Methyltransferases / metabolism*
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DNA Methylation
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Female
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Gene Expression Regulation, Neoplastic
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Humans
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Hypoxia-Inducible Factor 1, alpha Subunit / genetics
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Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
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Insulin Receptor Substrate Proteins / genetics*
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Insulin Receptor Substrate Proteins / metabolism
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MicroRNAs / genetics*
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Middle Aged
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Mitogen-Activated Protein Kinases / metabolism
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Neoplasm Grading
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Neovascularization, Pathologic / genetics*
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Phosphatidylinositol 3-Kinases / metabolism
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Promoter Regions, Genetic
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Proto-Oncogene Proteins c-akt / metabolism
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Receptor, IGF Type 1 / genetics*
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Receptor, IGF Type 1 / metabolism
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Signal Transduction
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Vascular Endothelial Growth Factor A / genetics
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Vascular Endothelial Growth Factor A / metabolism
Substances
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Hypoxia-Inducible Factor 1, alpha Subunit
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IRS1 protein, human
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Insulin Receptor Substrate Proteins
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MIRN148 microRNA, human
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MIRN152 microRNA, human
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MicroRNAs
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Vascular Endothelial Growth Factor A
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DNA (Cytosine-5-)-Methyltransferase 1
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DNA (Cytosine-5-)-Methyltransferases
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DNMT1 protein, human
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Phosphatidylinositol 3-Kinases
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Receptor, IGF Type 1
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Proto-Oncogene Proteins c-akt
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Extracellular Signal-Regulated MAP Kinases
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Mitogen-Activated Protein Kinases