Abstract
The basal-like subtype of breast cancer has an aggressive clinical behavior compared to that of the luminal subtype. We identified the microRNAs (miRNAs) miR-221 and miR-222 (miR-221/222) as basal-like subtype-specific miRNAs and showed that expression of miR-221/222 decreased expression of epithelial-specific genes and increased expression of mesenchymal-specific genes, and increased cell migration and invasion in a manner characteristic of the epithelial-to-mesenchymal transition (EMT). The transcription factor FOSL1 (also known as Fra-1), which is found in basal-like breast cancers but not in the luminal subtype, stimulated the transcription of miR-221/222, and the abundance of these miRNAs decreased with inhibition of the epidermal growth factor receptor (EGFR) or MEK (mitogen-activated or extracellular signal-regulated protein kinase kinase), placing miR-221/222 downstream of the RAS pathway. Furthermore, miR-221/222-mediated reduction in E-cadherin abundance depended on their targeting the 3' untranslated region of the GATA family transcriptional repressor TRPS1 (tricho-rhino-phalangeal syndrome type 1), which inhibited EMT by decreasing ZEB2 (zinc finger E-box-binding homeobox2) expression. We conclude that by promoting EMT, miR-221/222 may contribute to the more aggressive clinical behavior of basal-like breast cancers.
MeSH terms
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3' Untranslated Regions / genetics
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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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DNA-Binding Proteins / biosynthesis*
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DNA-Binding Proteins / genetics
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Epithelial-Mesenchymal Transition*
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ErbB Receptors / genetics
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ErbB Receptors / metabolism
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Female
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Gene Expression Regulation, Neoplastic*
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Homeodomain Proteins / genetics
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Homeodomain Proteins / metabolism
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Humans
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MAP Kinase Kinase Kinases / genetics
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MAP Kinase Kinase Kinases / metabolism
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MicroRNAs / biosynthesis*
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MicroRNAs / genetics
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Proto-Oncogene Proteins c-fos / genetics
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Proto-Oncogene Proteins c-fos / metabolism
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RNA, Neoplasm / biosynthesis*
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RNA, Neoplasm / genetics
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Repressor Proteins / genetics
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Repressor Proteins / metabolism
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Transcription Factors / biosynthesis*
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Transcription Factors / genetics
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Zinc Finger E-box Binding Homeobox 2
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ras Proteins / genetics
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ras Proteins / metabolism
Substances
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3' Untranslated Regions
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DNA-Binding Proteins
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Homeodomain Proteins
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MIRN221 microRNA, human
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MIRN222 microRNA, human
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MicroRNAs
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Proto-Oncogene Proteins c-fos
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RNA, Neoplasm
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Repressor Proteins
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TRPS1 protein, human
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Transcription Factors
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ZEB2 protein, human
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Zinc Finger E-box Binding Homeobox 2
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fos-related antigen 1
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EGFR protein, human
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ErbB Receptors
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MAP Kinase Kinase Kinases
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ras Proteins
Associated data
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GEO/GSE10843
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GEO/GSE12790
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GEO/GSE29327