MicroRNA-519a is a novel oncomir conferring tamoxifen resistance by targeting a network of tumour-suppressor genes in ER+ breast cancer
Date
2014Source Title
Journal of Pathology
Print ISSN
0022-3417
Publisher
John Wiley and Sons Ltd
Volume
233
Issue
4
Pages
368 - 379
Language
English
Type
ArticleItem Usage Stats
206
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102
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Abstract
Tamoxifen is an endocrine therapy which is administered to up to 70% of all breast cancer patients with oestrogen receptor alpha (ERα) expression. Despite the initial response, most patients eventually acquire resistance to the drug. MicroRNAs (miRNAs) are a class of small non-coding RNAs which have the ability to post-transcriptionally regulate genes. Although the role of a few miRNAs has been described in tamoxifen resistance at the single gene/target level, little is known about how concerted actions of miRNAs targeting biological networks contribute to resistance. Here we identified the miRNA cluster, C19MC, which harbours around 50 mature miRNAs, to be up-regulated in resistant cells, with miRNA-519a being the most highly up-regulated. We could demonstrate that miRNA-519a regulates tamoxifen resistance using gain- and loss-of-function testing. By combining functional enrichment analysis and prediction algorithms, we identified three central tumour-suppressor genes (TSGs) in PI3K signalling and the cell cycle network as direct target genes of miR-519a. Combined expression of these target genes correlated with disease-specific survival in a cohort of tamoxifen-treated patients. We identified miRNA-519a as a novel oncomir in ER+ breast cancer cells as it increased cell viability and cell cycle progression as well as resistance to tamoxifen-induced apoptosis. Finally, we could show that elevated miRNA-519a levels were inversely correlated with the target genes' expression and that higher expression of this miRNA correlated with poorer survival in ER+ breast cancer patients. Hence we have identified miRNA-519a as a novel oncomir, co-regulating a network of TSGs in breast cancer and conferring resistance to tamoxifen. Using inhibitors of such miRNAs may serve as a novel therapeutic approach to combat resistance to therapy as well as proliferation and evasion of apoptosis in breast cancer.
Keywords
Breast cancerC19MC cluster
Cell cycle network
MicroRNAs
Tamoxifen resistance
Estrogen receptor alpha
MicroRNA
Microrna 519a
Phosphatidylinositol 3 kinase
Small untranslated RNA
Tamoxifen
Unclassified drug
Algorithm
Apoptosis
Article
Breast cancer
Cell cycle progression
Cell viability
Controlled study
Correlation analysis
Disease specific survival
Estrogen receptor positive breast cancer
Gain of function mutation
Gene control
Gene expression
Gene targeting
Human
Human cell
Loss of function mutation
Nucleotide sequence
Priority journal
Tumor suppressor gene
Breast cancer
C19MC cluster
Cell cycle network
MicroRNAs
Tamoxifen resistance
Antineoplastic Agents, Hormonal
Apoptosis
Breast Neoplasms
Cell Cycle
Cell Line, Tumor
Drug Resistance, Neoplasm
Estrogen Receptor alpha
Female
Gene Expression Regulation, Neoplastic
Genes, Tumor Suppressor
Humans
MicroRNAs
Pharmacogenetics
Phosphatidylinositol 3-Kinases
Signal Transduction
Tamoxifen
Tumor Markers, Biological
Permalink
http://hdl.handle.net/11693/26456Published Version (Please cite this version)
http://dx.doi.org/10.1002/path.4363Collections
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