16
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Quantifying Argonaute 2 (Ago2) expression to stratify breast cancer

      research-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Background

          Argonaute-2 (Ago2) is an essential component of microRNA biogenesis implicated in tumourigenesis. However Ago2 expression and localisation in breast cancer remains undetermined. The aim was to define Ago2 expression (mRNA and protein) and localisation in breast cancer, and investigate associations with clinicopathological details.

          Methods

          Ago2 protein was stained in breast cancer cell lines and tissue microarrays (TMAs), with intensity and localization assessed. Staining intensity was correlated with clinicopathological details. Using independent databases, Ago2 mRNA expression and gene alterations in breast cancer were investigated.

          Results

          In the breast cancer TMAs, 4 distinct staining intensities were observed (Negative, Weak, Moderate, Strong), with 64.2% of samples stained weak or negatively for Ago2 protein. An association was found between strong Ago2 staining and, the Her2 positive or basal subtypes, and between Ago2 intensity and receptor status (Estrogen or Progesterone). In tumours Ago2 mRNA expression correlated with reduced relapse free survival. Conversely, Ago2 mRNA was expressed significantly lower in SK-BR-3 (HER2 positive) and BT-20 (Basal/Triple negative) cell lines. Interestingly, high levels of Ago2 gene amplification (10–27%) were observed in breast cancer across multiple patient datasets. Importantly, knowledge of Ago2 expression improves predictions of breast cancer subtype by 20%, ER status by 15.7% and PR status by 17.5%.

          Conclusions

          Quantification of Ago2 improves the stratification of breast cancer and suggests a differential role for Ago2 in breast cancer subtypes, based on levels and cellular localisation. Further investigation of the mechanisms affecting Ago2 dysregulation will reveal insights into the molecular differences underpinning breast cancer subtypes.

          Electronic supplementary material

          The online version of this article (10.1186/s12885-019-5884-x) contains supplementary material, which is available to authorized users.

          Related collections

          Most cited references30

          • Record: found
          • Abstract: found
          • Article: not found

          Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal.

          The cBioPortal for Cancer Genomics (http://cbioportal.org) provides a Web resource for exploring, visualizing, and analyzing multidimensional cancer genomics data. The portal reduces molecular profiling data from cancer tissues and cell lines into readily understandable genetic, epigenetic, gene expression, and proteomic events. The query interface combined with customized data storage enables researchers to interactively explore genetic alterations across samples, genes, and pathways and, when available in the underlying data, to link these to clinical outcomes. The portal provides graphical summaries of gene-level data from multiple platforms, network visualization and analysis, survival analysis, patient-centric queries, and software programmatic access. The intuitive Web interface of the portal makes complex cancer genomics profiles accessible to researchers and clinicians without requiring bioinformatics expertise, thus facilitating biological discoveries. Here, we provide a practical guide to the analysis and visualization features of the cBioPortal for Cancer Genomics.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Origins and Mechanisms of miRNAs and siRNAs.

            Over the last decade, approximately 20-30 nucleotide RNA molecules have emerged as critical regulators in the expression and function of eukaryotic genomes. Two primary categories of these small RNAs--short interfering RNAs (siRNAs) and microRNAs (miRNAs)--act in both somatic and germline lineages in a broad range of eukaryotic species to regulate endogenous genes and to defend the genome from invasive nucleic acids. Recent advances have revealed unexpected diversity in their biogenesis pathways and the regulatory mechanisms that they access. Our understanding of siRNA- and miRNA-based regulation has direct implications for fundamental biology as well as disease etiology and treatment.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Argonaute2 is the catalytic engine of mammalian RNAi.

              Gene silencing through RNA interference (RNAi) is carried out by RISC, the RNA-induced silencing complex. RISC contains two signature components, small interfering RNAs (siRNAs) and Argonaute family proteins. Here, we show that the multiple Argonaute proteins present in mammals are both biologically and biochemically distinct, with a single mammalian family member, Argonaute2, being responsible for messenger RNA cleavage activity. This protein is essential for mouse development, and cells lacking Argonaute2 are unable to mount an experimental response to siRNAs. Mutations within a cryptic ribonuclease H domain within Argonaute2, as identified by comparison with the structure of an archeal Argonaute protein, inactivate RISC. Thus, our evidence supports a model in which Argonaute contributes "Slicer" activity to RISC, providing the catalytic engine for RNAi.
                Bookmark

                Author and article information

                Contributors
                mckc86@gmail.com
                A.PRAKASH2@nuigalway.ie
                emma.holian@nuigalway.ie
                andrewmcguire@rcsi.ie
                olga.kahlinina@nuigalway.ie
                liaashalaby@gmail.com
                Catherine.curran@nuigalway.ie
                mark.webber@nuigalway.ie
                grace.callagy@nuigalway.ie
                emer.bourke@nuigalway.ie
                michael.kerin@nuigalway.ie
                0000-0002-3155-0334 , james.brown@nuigalway.ie
                Journal
                BMC Cancer
                BMC Cancer
                BMC Cancer
                BioMed Central (London )
                1471-2407
                19 July 2019
                19 July 2019
                2019
                : 19
                : 712
                Affiliations
                [1 ]ISNI 0000 0004 0488 0789, GRID grid.6142.1, Discipline of Surgery, School of Medicine, Lambe institute for Translational Research, , National University of Ireland, ; Galway, Ireland
                [2 ]ISNI 0000 0004 0488 0789, GRID grid.6142.1, Discipline of Pathology, School of Medicine, Lambe Institute for Translational Research, , National University of Ireland, ; Galway, Ireland
                [3 ]ISNI 0000 0004 0488 0789, GRID grid.6142.1, School of Mathematics, Statistics and Applied Mathematics, , National University of Ireland, ; Galway, Ireland
                Author information
                http://orcid.org/0000-0002-3155-0334
                Article
                5884
                10.1186/s12885-019-5884-x
                6642579
                31324173
                286266e0-7310-4c30-8372-79d3a8a7b7c8
                © The Author(s). 2019

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 2 August 2018
                : 26 June 2019
                Funding
                Funded by: Breast Cancer Research
                Award ID: .
                Funded by: Breast Cancer Research
                Award ID: .
                Award ID: .
                Award ID: .
                Award ID: .
                Categories
                Research Article
                Custom metadata
                © The Author(s) 2019

                Oncology & Radiotherapy
                ago2,eif2c2,staining,tumour,ihc,pattern,argonaute 2,mirna,microrna,breast,cancer,midbody,cytoplasmic,intensity,expression,mrna,biomarker,survival,disease,relapse,dfs,rfs,gene,amplification

                Comments

                Comment on this article