title: The role and regulatory mechanism of 14-3-3 sigma in human breast cancer.
abstract: OBJECTIVE
  14-3-3 sigma (σ) is considered to be an important tumor suppressor and decreased expression of the same has been reported in many malignant tumors by hypermethylation at its promoter or ubiquitin-mediated proteolysis by estrogen-responsive ring finger protein (Efp). In this study, we investigated the significance of 14-3-3 σ expression in human breast cancer and its regulatory mechanism.
  
  
  METHODS
  Efp was silenced using small interfering RNA (siRNA) in the MCF-7 breast cancer cell line in order to examine its influence on the level of 14-3-3 σ protein. The methylation status of the 14-3-3 σ promoter was also evaluated by methylation-specific polymerase chain reaction (PCR). The expression of Efp and 14-3-3 σ in 220 human breast carcinoma tissues was assessed by immunohistochemistry. Other clinicopathological parameters were also evaluated.
  
  
  RESULTS
  Silencing Efp in the MCF-7 breast cancer cell line resulted in increased expression of 14-3-3 σ. The Efp-positive human breast cancers were more frequently 14-3-3 σ-negative (60.5% vs. 39.5%). Hypermethylation of 14-3-3 σ was common (64.9%) and had an inverse association with 14-3-3 σ positivity (p=0.072). Positive 14-3-3 σ expression was significantly correlated with poor prognosis: disease-free survival (p=0.008) and disease-specific survival (p=0.009).
  
  
  CONCLUSIONS
  Our data suggests that in human breast cancer, the regulation of 14-3-3 σ may involve two mechanisms: ubiquitin-mediated proteolysis by Efp and downregulation by hypermethylation. However, the inactivation of 14-3-3 σ is probably achieved mainly by hypermethylation. Interestingly, 14-3-3 σ turned out to be a very significant poor prognostic indicator, which is in contrast to its previously known function as a tumor suppressor, suggesting a different role of 14-3-3 σ in breast cancer.
authors.affiliation: Department of Surgery, Cheil General Hospital & Women's Health Care Center, Catholic Kwandong University College of Medicine, Seoul, Korea.
authors.forename: SeungSang
authors.initials: S
authors.lastname: Ko
authors.affiliation: Department of Pathology, CHA Gangnam Medical Center, CHA University, Seoul, Korea.
authors.forename: Ji Young
authors.initials: JY
authors.lastname: Kim
authors.affiliation: Department of Surgery, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Joon
authors.initials: J
authors.lastname: Jeong
authors.affiliation: Department of Anatomy, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Jong Eun
authors.initials: JE
authors.lastname: Lee
authors.affiliation: Department of Pathology, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Woo Ick
authors.initials: WI
authors.lastname: Yang
authors.affiliation: Department of Pathology, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Woo Hee
authors.initials: WH
authors.lastname: Jung
keywords: Breast neoplasms; Estrogen-responsive finger protein; Methylation; SFN protein