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      MicroRNA-519a is a novel oncomir conferring tamoxifen resistance by targeting a network of tumour-suppressor genes in ER+ breast cancer

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      Author(s)
      Ward, A.
      Shukla, K.
      Balwierz, A.
      Soons, Z.
      König, R.
      Sahin, O.
      Wiemann, S.
      Date
      2014
      Source Title
      Journal of Pathology
      Print ISSN
      0022-3417
      Publisher
      John Wiley and Sons Ltd
      Volume
      233
      Issue
      4
      Pages
      368 - 379
      Language
      English
      Type
      Article
      Item Usage Stats
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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 cancer
      C19MC 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/11693/26456
      Published Version (Please cite this version)
      http://dx.doi.org/10.1002/path.4363
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      • Department of Molecular Biology and Genetics 512
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