title: Seven In Absentia Homolog 2 (SIAH2) downregulation is associated with tamoxifen resistance in MCF-7 breast cancer cells.
abstract: BACKGROUND
  A significant percentage of estrogen receptor (ER)-positive breast cancers are resistant to tamoxifen therapy. Seven in Absentia Homolog 2 (SIAH2), an E3 ubiquitin protein ligase, has been shown to be associated with resistance to antiestrogens. We sought to assess its role in the resistance of a breast cancer cell line, MCF-7, to the ER antagonist, tamoxifen.
  
  
  METHODS
  A bioinformatic approach was used for the analysis of SIAH2 expression in breast cancer. MCF-7 and MDA-MB-231, which are ER-positive and -negative breast cancer cell lines, respectively, were used for in vitro studies. SIAH2 and ER-α were selectively knocked down in these cell lines with small-interfering RNAs. Knockdowns were confirmed with Western blot analysis and quantitative real-time polymerase chain reaction. Cells with SIAH2 knockdown were treated with tamoxifen and compared with controls.
  
  
  RESULTS
  Knockdown of SIAH2 followed by treatment with tamoxifen resulted in a significant decrease in the sensitivity of treated ER-positive cells. Of note, knockdown of SIAH2 resulted in downregulation of ER-α, whereas knockdown of ER-α had minimal effect on SIAH2. Consistent with this result, the bioinformatic analysis of clinical data revealed that SIAH2 expression is significantly correlated with ER positivity in human breast cancers, and low SIAH2 expression is associated with a poorer response to tamoxifen.
  
  
  CONCLUSIONS
  SIAH2 appears to be an important modulator of tamoxifen sensitivity in ER-positive MCF-7 cells, mediated, at least in part, through regulation of ER-α expression. Low expression of SIAH2 may be one of the mechanisms that contribute to tamoxifen resistance in human breast cancer.
authors.affiliation: Department of Surgery, St. Jude Children's Research Hospital, Memphis, Tennessee; Department of Surgery, University of Tennessee Health Science Center, Memphis, Tennessee.
authors.forename: Rodrigo B
authors.initials: RB
authors.lastname: Interiano
authors.affiliation: Department of Surgery, St. Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Oncology, The Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.
authors.forename: Adrian L
authors.initials: AL
authors.lastname: Harris
authors.affiliation: Department of Surgery, St. Jude Children's Research Hospital, Memphis, Tennessee; Department of Surgery, University of Tennessee Health Science Center, Memphis, Tennessee. Electronic address: andrew.davidoff@stjude.org.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Davidoff
mesh_terms: D001943:Breast Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000473:pathology; D019295:Computational Biology; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D004965:Estrogen Antagonists / Q000627:therapeutic use*; D047628:Estrogen Receptor alpha / Q000032:analysis; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D009687:Nuclear Proteins / Q000502:physiology*; D013629:Tamoxifen / Q000627:therapeutic use*; D044767:Ubiquitin-Protein Ligases / Q000502:physiology*; D000098563:Seven in Absentia Proteins
chemical_list: C506487:ESR1 protein, human; D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D009687:Nuclear Proteins; D013629:Tamoxifen; D044767:Ubiquitin-Protein Ligases; D000098563:Seven in Absentia Proteins
keywords: Breast cancer; Estrogen receptor; Resistance; SIAH2; Tamoxifen