title: MYC functions are specific in biological subtypes of breast cancer and confers resistance to endocrine therapy in luminal tumours.
abstract: BACKGROUND
  MYC is amplified in approximately 15% of breast cancers (BCs) and is associated with poor outcome. c-MYC protein is multi-faceted and participates in many aspects of cellular function and is linked with therapeutic response in BCs. We hypothesised that the functional role of c-MYC differs between molecular subtypes of BCs.
  
  
  METHODS
  We therefore investigated the correlation between c-MYC protein expression and other proteins involved in different cellular functions together with clinicopathological parameters, patients' outcome and treatments in a large early-stage molecularly characterised series of primary invasive BCs (n=1106) using immunohistochemistry. The METABRIC BC cohort (n=1980) was evaluated for MYC mRNA expression and a systems biology approach utilised to identify genes associated with MYC in the different BC molecular subtypes.
  
  
  RESULTS
  High MYC and c-MYC expression was significantly associated with poor prognostic factors, including grade and basal-like BCs. In luminal A tumours, c-MYC was associated with ATM (P=0.005), Cyclin B1 (P=0.002), PIK3CA (P=0.009) and Ki67 (P<0.001). In contrast, in basal-like tumours, c-MYC showed positive association with Cyclin E (P=0.003) and p16 (P=0.042) expression only. c-MYC was an independent predictor of a shorter distant metastases-free survival in luminal A LN+ tumours treated with endocrine therapy (ET; P=0.013). In luminal tumours treated with ET, MYC mRNA expression was associated with BC-specific survival (P=0.001). In ER-positive tumours, MYC was associated with expression of translational genes while in ER-negative tumours it was associated with upregulation of glucose metabolism genes.
  
  
  CONCLUSIONS
  c-MYC function is associated with specific molecular subtypes of BCs and its overexpression confers resistance to ET. The diverse mechanisms of c-MYC function in the different molecular classes of BCs warrants further investigation particularly as potential therapeutic targets.
authors.affiliation: Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham City Hospital, Hucknall Road, Nottingham NG5 1PB, UK.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Green
authors.affiliation: Cellular Pathology, Nottingham University Hospitals NHS Trust, Hucknall Road, Nottingham NG5 1PB, UK.
authors.forename: Mohammed A
authors.initials: MA
authors.lastname: Aleskandarany
authors.affiliation: School of Science and Technology, Nottingham Trent University, Nottingham NG11 8NS, UK.
authors.forename: Devika
authors.initials: D
authors.lastname: Agarwal
authors.affiliation: Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham City Hospital, Hucknall Road, Nottingham NG5 1PB, UK.|Cellular Pathology, Nottingham University Hospitals NHS Trust, Hucknall Road, Nottingham NG5 1PB, UK.
authors.forename: Somaia
authors.initials: S
authors.lastname: Elsheikh
authors.affiliation: Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham City Hospital, Hucknall Road, Nottingham NG5 1PB, UK.
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Nolan
authors.affiliation: Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham City Hospital, Hucknall Road, Nottingham NG5 1PB, UK.
authors.forename: Maria
authors.initials: M
authors.lastname: Diez-Rodriguez
authors.affiliation: Breast Institute, Nottingham University Hospitals NHS Trust, Hucknall Road, Nottingham NG5 1PB, UK.
authors.forename: R Douglas
authors.initials: RD
authors.lastname: Macmillan
authors.affiliation: School of Science and Technology, Nottingham Trent University, Nottingham NG11 8NS, UK.
authors.forename: Graham R
authors.initials: GR
authors.lastname: Ball
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE.
authors.forename: Carlos
authors.initials: C
authors.lastname: Caldas
authors.affiliation: Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham City Hospital, Hucknall Road, Nottingham NG5 1PB, UK.
authors.forename: Srinivasan
authors.initials: S
authors.lastname: Madhusudan
authors.affiliation: Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham City Hospital, Hucknall Road, Nottingham NG5 1PB, UK.|Cellular Pathology, Nottingham University Hospitals NHS Trust, Hucknall Road, Nottingham NG5 1PB, UK.
authors.forename: Ian O
authors.initials: IO
authors.lastname: Ellis
authors.affiliation: Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham City Hospital, Hucknall Road, Nottingham NG5 1PB, UK.|Cellular Pathology, Nottingham University Hospitals NHS Trust, Hucknall Road, Nottingham NG5 1PB, UK.
authors.forename: Emad A
authors.initials: EA
authors.lastname: Rakha
mesh_terms: D000368:Aged; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics; D014408:Biomarkers, Tumor / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology*; D058534:Class I Phosphatidylinositol 3-Kinases; D056744:Cyclin B1 / Q000235:genetics; D019927:Cyclin E / Q000235:genetics; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D055098:Endocrine Cells / Q000502:physiology*; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D011379:Prognosis; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics
chemical_list: D064007:Ataxia Telangiectasia Mutated Proteins; D014408:Biomarkers, Tumor; D058534:Class I Phosphatidylinositol 3-Kinases; D056744:Cyclin B1; D019927:Cyclin E; D019869:Phosphatidylinositol 3-Kinases; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases; C484760:PIK3CA protein, human