title: Decreased expression and prognostic role of cytoplasmic BRSK1 in human breast carcinoma: correlation with Jab1 stability and PI3K/Akt pathway.
abstract: OBJECTIVE
  Jun activation domain-binding protein 1 (Jab1) was overexpressed in breast cancer, which was involved in degradation of the cyclin-dependent kinase inhibitor p27(Kip1). The objective of this study was to examine the effect of brain specific kinase 1 (BRSK1) expression on Jab1 over-expression and related signaling pathway in breast cancer.
  
  
  METHODS
  Immunohistochemical analysis was performed in 95 human breast carcinoma samples and the data were correlated with clinicopathologic features. Furthermore, Western blot analysis was performed for BRSK1 and Jab1 in breast carcinoma samples and cell lines to evaluate their protein levels and molecular interaction.
  
  
  RESULTS
  We found that the cytoplasmic BRSK1 expression was inversely associated with Jab1 expression (P<0.01) and correlated significantly with histologic grade (P=0.006), however nuclear BRSK1 expression couldn't obtain similar results. Kaplan-Meier analysis revealed that survival curves of low versus high expressers of cytoplasmic BRSK1 and Jab1 showed a highly significant separation in breast cancer (P<0.01). While in vitro, following release of breast cancer cell lines from serum starvation, the expression of Jab1, phosphor-Akt (p-Akt) was up-regulated, whereas BRSK1 and p27(Kip1) were decreased. Treatment of phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 could diminish Jab1 expression but increase BRSK1 expression. In addition, we employed siRNA technique to knock down Jab1 and/or BRSK1 expression and observed their effects on MDA-MB-231 cell growth.
  
  
  CONCLUSIONS
  BRSK1 is a novel tumor suppressor in breast cancer which inversely correlated with Jab1 expression, may involve in the restoring Jab1-induced suppression of p27(Kip1) and may regulate cell cycle through the PI3K/Akt pathway.
authors.affiliation: Department of General Surgery, the Affiliated Hospital of Nantong University, Medical College of Nantong University, Nantong 226001, Jiangsu, PR China.
authors.forename: Hua
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of General Surgery, the Affiliated Hospital of Nantong University, Medical College of Nantong University, Nantong 226001, Jiangsu, PR China.
authors.forename: Xiao-Bing
authors.initials: XB
authors.lastname: Liu
authors.affiliation: Department of Neurology, Affiliated Hospital of Nantong University, Medical College of Nantong University, Nantong 226001, Jiangsu, PR China.
authors.forename: Jia-Hui
authors.initials: JH
authors.lastname: Chen
authors.affiliation: Department of General Surgery, the Affiliated Hospital of Nantong University, Medical College of Nantong University, Nantong 226001, Jiangsu, PR China.
authors.forename: Qing-Qing
authors.initials: QQ
authors.lastname: Wang
authors.affiliation: Department of General Surgery, the Affiliated Hospital of Nantong University, Medical College of Nantong University, Nantong 226001, Jiangsu, PR China.
authors.forename: Jin-Peng
authors.initials: JP
authors.lastname: Chen
authors.affiliation: Department of General Surgery, the Affiliated Hospital of Nantong University, Medical College of Nantong University, Nantong 226001, Jiangsu, PR China.
authors.forename: Jun-Fei
authors.initials: JF
authors.lastname: Xu
authors.affiliation: Department of General Surgery, the Affiliated Hospital of Nantong University, Medical College of Nantong University, Nantong 226001, Jiangsu, PR China.
authors.forename: Chen-Yi
authors.initials: CY
authors.lastname: Sheng
authors.affiliation: Department of General Surgery, the Affiliated Hospital of Nantong University, Medical College of Nantong University, Nantong 226001, Jiangsu, PR China. Electronic address: niqichao2013@163.com.
authors.forename: Qi-Chao
authors.initials: QC
authors.lastname: Ni
mesh_terms: D000328:Adult; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000175:diagnosis / Q000378:metabolism*; D000075686:COP9 Signalosome Complex; D002277:Carcinoma / Q000175:diagnosis / Q000378:metabolism*; D002867:Chromones / Q000494:pharmacology; D003593:Cytoplasm / Q000378:metabolism; D004795:Enzyme Stability; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D061986:MCF-7 Cells; D008875:Middle Aged; D009025:Morpholines / Q000494:pharmacology; D010447:Peptide Hydrolases / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D014408:Biomarkers, Tumor; D000075686:COP9 Signalosome Complex; D002867:Chromones; D047908:Intracellular Signaling Peptides and Proteins; D009025:Morpholines; D010447:Peptide Hydrolases; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C523084:BRSK1 protein, human; C501488:COPS5 protein, human
keywords: BRSK1; Breast cancer; Jab1; PI3K/Akt; Prognosis