title: The expression of the ubiquitin ligase SIAH2 (seven in absentia homolog 2) is mediated through gene copy number in breast cancer and is associated with a basal-like phenotype and p53 expression.
abstract: BACKGROUND
  The seven in absentia homolog 2 (SIAH2) protein plays a significant role in the hypoxic response by regulating the abundance of hypoxia-inducible factor-α; however, its role in breast carcinoma is unclear. We investigated the frequency and expression pattern of SIAH2 in two independent cohorts of sporadic breast cancers.
  
  
  METHODS
  Immunohistochemical evaluation of SIAH2protein expression was conducted in normal breast tissues and in tissue microarrays comprising ductal carcinoma in situ (DCIS) and a cohort of invasive breast carcinomas. Correlation analysis was performed between SIAH2 and clinicopathological variables and intrinsic breast cancer subgroups and validated in a cohort of 293 invasive ductal carcinomas. Promoter methylation, gene copy number and mRNA expression of SIAH2 were determined in a panel of basal-like tumors and cell lines.
  
  
  RESULTS
  There was a significant increase in nuclear SIAH2 expression from normal breast tissues through to DCIS and progression to invasive cancers. A significant inverse correlation was apparent between SIAH2 and estrogen receptor and progesterone receptor and a positive association with tumor grade, HER2, p53 and an intrinsic basal-like subtype. Logistic regression analysis confirmed the significant positive association between SIAH2 expression and the basal-like phenotype. No SIAH2 promoter methylation was identified, yet there was a significant correlation between SIAH2 mRNA and gene copy number. SIAH2-positive tumors were associated with a shorter relapse-free survival in univariate but not multivariate analysis.
  
  
  CONCLUSIONS
  SIAH2 expression is upregulated in basal-like breast cancers via copy number changes and/or transcriptional activation by p53 and is likely to be partly responsible for the enhanced hypoxic drive through abrogation of the prolyl hydroxylases.
authors.affiliation: Department of Pathology, Peter MacCallum Cancer Centre, Locked Bag 1 A'Beckett Street, Melbourne, Victoria 8006, Australia.
authors.forename: Peter
authors.initials: P
authors.lastname: Chan
authors.forename: Andreas
authors.initials: A
authors.lastname: Möller
authors.forename: Mira C P
authors.initials: MC
authors.lastname: Liu
authors.forename: Jaclyn E
authors.initials: JE
authors.lastname: Sceneay
authors.forename: Christina S F
authors.initials: CS
authors.lastname: Wong
authors.forename: Nic
authors.initials: N
authors.lastname: Waddell
authors.forename: Katie T
authors.initials: KT
authors.lastname: Huang
authors.forename: Alexander
authors.initials: A
authors.lastname: Dobrovic
authors.forename: Ewan K A
authors.initials: EK
authors.lastname: Millar
authors.forename: Sandra A
authors.initials: SA
authors.lastname: O'Toole
authors.forename: Catriona M
authors.initials: CM
authors.lastname: McNeil
authors.forename: Robert L
authors.initials: RL
authors.lastname: Sutherland
authors.forename: David D
authors.initials: DD
authors.lastname: Bowtell
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Fox
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D015331:Cohort Studies; D019175:DNA Methylation; D005260:Female; D018628:Gene Dosage; D015870:Gene Expression; D006801:Humans; D053208:Kaplan-Meier Estimate; D042361:Mammary Glands, Human / Q000378:metabolism; D008875:Middle Aged; D009367:Neoplasm Staging; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D011401:Promoter Regions, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult; D000098563:Seven in Absentia Proteins
chemical_list: D009687:Nuclear Proteins; D016159:Tumor Suppressor Protein p53; D044767:Ubiquitin-Protein Ligases; D000098563:Seven in Absentia Proteins