miR-139-5p is a regulator of metastatic pathways in breast cancer

Metastasis is a complex, multistep process involved in the progression of cancer from a localized primary tissue to distant sites, often characteristic of the more aggressive forms of this disease. Despite being studied in great detail in recent years, the mechanisms that govern this process remain...

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Bibliographic Details
Published in:RNA (Cambridge) 2013-12, Vol.19 (12), p.1767-1780
Main Authors: Krishnan, Keerthana, Steptoe, Anita L, Martin, Hilary C, Pattabiraman, Diwakar R, Nones, Katia, Waddell, Nic, Mariasegaram, Mythily, Simpson, Peter T, Lakhani, Sunil R, Vlassov, Alexander, Grimmond, Sean M, Cloonan, Nicole
Format: Article
Language:English
Subjects:
Base Sequence
Binding Sites
Carcinoma, Ductal, Breast - genetics
Carcinoma, Ductal, Breast - metabolism
Carcinoma, Ductal, Breast - secondary
Cell Line, Tumor
Cell Movement
Cell Proliferation
DNA Replication
Female
Gene Expression
Gene Expression Regulation, Neoplastic
Humans
Intracellular Signaling Peptides and Proteins - genetics
Intracellular Signaling Peptides and Proteins - metabolism
MicroRNAs - physiology
Neoplasm Invasiveness
RNA Interference
Signal Transduction
Triple Negative Breast Neoplasms - genetics
Triple Negative Breast Neoplasms - metabolism
Triple Negative Breast Neoplasms - pathology
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Summary:Metastasis is a complex, multistep process involved in the progression of cancer from a localized primary tissue to distant sites, often characteristic of the more aggressive forms of this disease. Despite being studied in great detail in recent years, the mechanisms that govern this process remain poorly understood. In this study, we identify a novel role for miR-139-5p in the inhibition of breast cancer progression. We highlight its clinical relevance by reviewing miR-139-5p expression across a wide variety of breast cancer subtypes using in-house generated and online data sets to show that it is most frequently lost in invasive tumors. A biotin pull-down approach was then used to identify the mRNA targets of miR-139-5p in the breast cancer cell line MCF7. Functional enrichment analysis of the pulled-down targets showed significant enrichment of genes in pathways previously implicated in breast cancer metastasis (P < 0.05). Further bioinformatic analysis revealed a predicted disruption to the TGFβ, Wnt, Rho, and MAPK/PI3K signaling cascades, implying a potential role for miR-139-5p in regulating the ability of cells to invade and migrate. To corroborate this finding, using the MDA-MB-231 breast cancer cell line, we show that overexpression of miR-139-5p results in suppression of these cellular phenotypes. Furthermore, we validate the interaction between miR-139-5p and predicted targets involved in these pathways. Collectively, these results suggest a significant functional role for miR-139-5p in breast cancer cell motility and invasion and its potential to be used as a prognostic marker for the aggressive forms of breast cancer.
ISSN:1355-8382
1469-9001
DOI:10.1261/rna.042143.113