title: Expression of sphingosine 1-phosphate receptor 4 and sphingosine kinase 1 is associated with outcome in oestrogen receptor-negative breast cancer.
abstract: BACKGROUND
  We previously reported that sphingosine 1-phosphate receptor 4 (S1P(4)) is expressed and stimulates the ERK-1/2 pathway via a human epidermal growth factor receptor 2 (HER2)-dependent mechanism in oestrogen receptor-negative (ER(-)) MDA-MB-453 breast cancer cells.
  
  
  METHODS
  Clinical relevance of S1P(4) and sphingosine kinase 1 (SK1, which catalyses the formation of S1P) was assessed in a cohort of 140 ER(-) breast tumours by immunohistochemistry (IHC) and the weighted histoscore method. Additional evidence for a functional interaction between S1P(4) and SK1 and between HER2 and SK1 was obtained using MDA-MB-453 cells.
  
  
  RESULTS
  High S1P(4) expression is associated with shorter disease-free (P=0.014) and disease-specific survival (P=0.004), and was independent on multivariate analysis. In addition, patients with tumours that contain high and low levels of SK1 and S1P(4), respectively, have a significantly shorter disease-free survival (P=0.043) and disease-specific survival (P=0.033) compared with patients whose tumours contain both low S1P(4) and SK1 levels. In addition, high tumour expression of SK1 was significantly associated with shorter disease-specific survival (P=0.0001) in patients with HER2-positive tumours. Treatment of MDA-MB-453 cells with the SK1 inhibitor, SKi (2-(p-hydroxyanilino)-4-(p-chlorophenyl)thiazole) reduced the basal and S1P/S1P(4)-induced activation of ERK-1/2 and altered HER2 trafficking in these cells.
  
  
  CONCLUSIONS
  These findings highlight an important role for S1P(4) and SK1 in ER(-) breast cancer progression.
authors.affiliation: Cell Biology Group, SIPBS, University of Strathclyde, Glasgow, UK.
authors.forename: J
authors.initials: J
authors.lastname: Ohotski
authors.forename: J S
authors.initials: JS
authors.lastname: Long
authors.forename: C
authors.initials: C
authors.lastname: Orange
authors.forename: B
authors.initials: B
authors.lastname: Elsberger
authors.forename: E
authors.initials: E
authors.lastname: Mallon
authors.forename: J
authors.initials: J
authors.lastname: Doughty
authors.forename: S
authors.initials: S
authors.lastname: Pyne
authors.forename: N J
authors.initials: NJ
authors.lastname: Pyne
authors.forename: J
authors.initials: J
authors.lastname: Edwards
mesh_terms: D001943:Breast Neoplasms / Q000175:diagnosis / Q000378:metabolism*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000096:biosynthesis* / Q000378:metabolism; D011379:Prognosis; D011960:Receptors, Estrogen / Q000172:deficiency; D049349:Receptors, Lysosphingolipid / Q000096:biosynthesis*; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured; D000099157:Sphingosine Kinase
chemical_list: D017853:Phosphotransferases (Alcohol Group Acceptor); D011960:Receptors, Estrogen; D049349:Receptors, Lysosphingolipid; D000099157:Sphingosine Kinase