Expression of sphingosine 1-phosphate receptor 4 and sphingosine kinase 1 is associated with outcome in oestrogen receptor-negative breast cancer

Br J Cancer. 2012 Apr 10;106(8):1453-9. doi: 10.1038/bjc.2012.98. Epub 2012 Mar 29.


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.

Conclusion: These findings highlight an important role for S1P(4) and SK1 in ER(-) breast cancer progression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Breast Neoplasms / diagnosis
  • Breast Neoplasms / metabolism*
  • Female
  • Humans
  • Immunohistochemistry
  • Phosphotransferases (Alcohol Group Acceptor) / biosynthesis*
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism
  • Prognosis
  • Receptors, Estrogen / deficiency
  • Receptors, Lysosphingolipid / biosynthesis*
  • Treatment Outcome
  • Tumor Cells, Cultured


  • Receptors, Estrogen
  • Receptors, Lysosphingolipid
  • Phosphotransferases (Alcohol Group Acceptor)
  • sphingosine kinase