title: SIRT2: tumour suppressor or tumour promoter in operable breast cancer?
abstract: OBJECTIVE
  Sirtuins comprise a family of genes involved in cellular stress, survival and damage responses. They have been implicated in a range of diseases including cancer, with most information pertaining to their function in tumourigenesis being derived from in vitro studies, or model organisms. Their putative roles as tumour suppressors or tumour promoters remain to be validated in vivo. Little is known about their role in breast tumourigenesis. We sought to evaluate the seven sirtuin family members (SIRT1-7) in a human breast cancer cohort, in relation to clinico-pathological features and outcome of the disease.
  
  
  METHODS
  Immunohistochemical analysis of SIRT1-7 protein levels was undertaken in 392 oestrogen receptor (ER+ve) and 153 ER-ve breast tumour samples. SIRT1-7 transcriptional levels were assessed in normal (n=25), non-malignant (n=73) and malignant (n=70) breast tissue using Relative Quantitative Real Time PCR. Statistical analyses determined if SIRT1-7 transcription or protein expression was associated with clinical parameters or outcome.
  
  
  RESULTS
  In ER-ve tumours, high protein levels of nuclear SIRT2 were associated with reduced time to recurrence and disease-specific death. This association was only observed in Grade 3 tumours. In the ER+ve cohort, high SIRT2 nuclear levels were associated with shorter disease-free survival and time to recurrence whilst on Tamoxifen, in patients with Grade 3 tumours. Conversely, in Grade 2 tumours, high SIRT2 levels were associated with increased time to recurrence.
  
  
  CONCLUSIONS
  Our data suggest that SIRT2 is the sirtuin predominantly involved in breast tumourigenesis and prognosis. It indicates that SIRT2 acts as a tumour suppressor or tumour promoter dependent upon breast tumour grade.
authors.affiliation: Institute of Cancer Sciences, University of Glasgow, Glasgow G11 6NT, UK.
authors.forename: Liane M
authors.initials: LM
authors.lastname: McGlynn
authors.affiliation: Institute of Cancer Sciences, University of Glasgow, Glasgow G11 6NT, UK.
authors.forename: Samer
authors.initials: S
authors.lastname: Zino
authors.affiliation: Institute of Cancer Sciences, University of Glasgow, Glasgow G11 6NT, UK.
authors.forename: Alasdair I
authors.initials: AI
authors.lastname: MacDonald
authors.affiliation: Institute of Cancer Sciences, University of Glasgow, Glasgow G11 6NT, UK.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Curle
authors.affiliation: Institute of Cancer Sciences, University of Glasgow, Glasgow G11 6NT, UK.
authors.forename: Justice E
authors.initials: JE
authors.lastname: Reilly
authors.affiliation: Institute of Cancer Sciences, University of Glasgow, Glasgow G11 6NT, UK.
authors.forename: Zahra M A
authors.initials: ZM
authors.lastname: Mohammed
authors.affiliation: School of Medicine, University of Glasgow, Glasgow Royal Infirmary, Glasgow G4 0SF, UK.
authors.forename: Donald C
authors.initials: DC
authors.lastname: McMillan
authors.affiliation: School of Medicine, Department of Pathology, University of Glasgow, Southern General Hospital, Glasgow G51 4TF, UK.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Mallon
authors.affiliation: School of Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK.
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Payne
authors.affiliation: Institute of Cancer Sciences, University of Glasgow, Glasgow G11 6NT, UK.
authors.forename: Joanne
authors.initials: J
authors.lastname: Edwards
authors.affiliation: Institute of Cancer Sciences, University of Glasgow, Glasgow G11 6NT, UK. Electronic address: paul.shiels@glasgow.ac.uk.
authors.forename: Paul G
authors.initials: PG
authors.lastname: Shiels
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D001940:Breast / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D060787:Neoplasm Grading; D009364:Neoplasm Recurrence, Local; D011379:Prognosis; D011960:Receptors, Estrogen / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D056565:Sirtuin 2 / Q000235:genetics / Q000378:metabolism*; D013629:Tamoxifen / Q000627:therapeutic use; D016896:Treatment Outcome; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D018931:Antineoplastic Agents, Hormonal; D014408:Biomarkers, Tumor; D007527:Isoenzymes; D011960:Receptors, Estrogen; D025521:Tumor Suppressor Proteins; D013629:Tamoxifen; C474199:SIRT2 protein, human; D056565:Sirtuin 2
keywords: Biological ageing; Biomarker; Breast cancer; Immunohistochemistry; Sirtuins; Tumour grade; Tumour promoter; Tumour suppressor