title: miR-139-5p is a regulator of metastatic pathways in breast cancer.
abstract: 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.
authors.forename: Keerthana
authors.initials: K
authors.lastname: Krishnan
authors.forename: Anita L
authors.initials: AL
authors.lastname: Steptoe
authors.forename: Hilary C
authors.initials: HC
authors.lastname: Martin
authors.forename: Diwakar R
authors.initials: DR
authors.lastname: Pattabiraman
authors.forename: Katia
authors.initials: K
authors.lastname: Nones
authors.forename: Nic
authors.initials: N
authors.lastname: Waddell
authors.forename: Mythily
authors.initials: M
authors.lastname: Mariasegaram
authors.forename: Peter T
authors.initials: PT
authors.lastname: Simpson
authors.forename: Sunil R
authors.initials: SR
authors.lastname: Lakhani
authors.forename: Alexander
authors.initials: A
authors.lastname: Vlassov
authors.forename: Sean M
authors.initials: SM
authors.lastname: Grimmond
authors.forename: Nicole
authors.initials: N
authors.lastname: Cloonan
mesh_terms: D001483:Base Sequence; D001665:Binding Sites; D018270:Carcinoma, Ductal, Breast / Q000235:genetics* / Q000378:metabolism / Q000556:secondary; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D004261:DNA Replication; D005260:Female; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D035683:MicroRNAs / Q000502:physiology*; D009361:Neoplasm Invasiveness; D034622:RNA Interference; D015398:Signal Transduction; D064726:Triple Negative Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C555098:MIRN139 microRNA, human; D035683:MicroRNAs
keywords: biomarker; breast cancer; miRNA