title: Further evidence to support bimodality of oestrogen receptor expression in breast cancer.
abstract: OBJECTIVE
  Although oestrogen receptor (ER)-negative breast cancers (BCs) do not respond to hormone therapy, the response of ER-positive BCs is reported to be variable, which may suggest a dose-dependent effect. The aim of this study was to assess the pattern of ER expression in BCs at the protein (immunohistochemistry) and transcriptome (microarray-based gene expression) levels.
  
  
  RESULTS
  ER immunohistochemical (IHC) expression was assessed in a large series of BCs, including 3649 core biopsies and 1892 cases prepared as tissue microarrays (TMAs) stained with specific antibodies. ESR1 mRNA expression was assessed in the METABRIC study (1980 cases), by the use of the Linear Models for Microarray Data (limma) software, and the results were compared with protein levels. IHC data confirmed the bimodality of ER expression, with 92.2% and 89.2% of the cases showing completely negative (<1%) or highly positive (≥70%) expression on the cores and TMAs, respectively. Weakly positive cases (1-10%) and intermediately positive (11-69%) cases were infrequent (2.7% and 5.1%, and 1.6% and 9.2%, in cores and TMAs, respectively), and did not show survival difference from ER-negative tumours. When full-face sections of the corresponding excision specimens were immunostained, 47% of the ER-low/intermediate group were deemed to be ER-negative. Transcriptomic data not only showed a significant correlation between ESR1 mRNA and protein expression levels, but also confirmed the bimodality of ER expression at the mRNA level.
  
  
  CONCLUSIONS
  Our study provides further evidence that ER expression is bimodal, and that it is observed at both the mRNA and protein levels. The reported poor survival of BC patients with low ER expression in the early clinical trials may be related to the inclusion of ER-negative cases.
authors.affiliation: Division of Cancer and Stem Cells, School of Medicine, The University of Nottingham and Nottingham University Hospitals NHS Trust, Nottingham City Hospital, Nottingham, UK.|Department of Pathology, Faculty of Medicine, University of Benghazi, Benghazi, Libya.
authors.forename: Abir A
authors.initials: AA
authors.lastname: Muftah
authors.affiliation: Division of Cancer and Stem Cells, School of Medicine, The University of Nottingham and Nottingham University Hospitals NHS Trust, Nottingham City Hospital, Nottingham, UK.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Aleskandarany
authors.affiliation: Division of Cancer and Stem Cells, School of Medicine, The University of Nottingham and Nottingham University Hospitals NHS Trust, Nottingham City Hospital, Nottingham, UK.
authors.forename: Sultan N
authors.initials: SN
authors.lastname: Sonbul
authors.affiliation: Division of Cancer and Stem Cells, School of Medicine, The University of Nottingham and Nottingham University Hospitals NHS Trust, Nottingham City Hospital, Nottingham, UK.
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Nolan
authors.affiliation: Division of Cancer and Stem Cells, School of Medicine, The University of Nottingham and Nottingham University Hospitals NHS Trust, Nottingham City Hospital, Nottingham, UK.
authors.forename: Maria
authors.initials: M
authors.lastname: Diez Rodriguez
authors.affiliation: Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, UK.
authors.forename: Carlos
authors.initials: C
authors.lastname: Caldas
authors.affiliation: Division of Cancer and Stem Cells, School of Medicine, The University of Nottingham and Nottingham University Hospitals NHS Trust, Nottingham City Hospital, Nottingham, UK.
authors.forename: Ian O
authors.initials: IO
authors.lastname: Ellis
authors.affiliation: Division of Cancer and Stem Cells, School of Medicine, The University of Nottingham and Nottingham University Hospitals NHS Trust, Nottingham City Hospital, Nottingham, UK.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Green
authors.affiliation: Division of Cancer and Stem Cells, School of Medicine, The University of Nottingham and Nottingham University Hospitals NHS Trust, Nottingham City Hospital, Nottingham, UK.
authors.forename: Emad A
authors.initials: EA
authors.lastname: Rakha
mesh_terms: D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D015331:Cohort Studies; D047628:Estrogen Receptor alpha / Q000096:biosynthesis*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D046888:Tissue Array Analysis
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha
keywords: 
  ESR
  ; bimodality; breast cancer; expression pattern; oestrogen receptor