Ohotski, J., Long, J.S., Orange, C., Elsberger, B., Doughty, J., Pyne, S., Pyne, N.J. and Edwards, J. (2012) Expression of sphingosine 1-phosphate receptor 4 and sphingosine kinase 1 is associated with outcome in oestrogen receptor-negative breast cancer. British Journal of Cancer, 106(8), pp. 1453-1459. (doi: 10.1038/bjc.2012.98)
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Abstract
Background: We previously reported that sphingosine 1-phosphate receptor 4 (S1P4) 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 S1P4 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 S1P4 and SK1 and between HER2 and SK1 was obtained using MDA-MB-453 cells. Results: High S1P4 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 S1P4, 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 S1P4 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/S1P4-induced activation of ERK-1/2 and altered HER2 trafficking in these cells. Conclusion: These findings highlight an important role for S1P4 and SK1 in ER− breast cancer progression.
| Item Type: | Articles |
|---|---|
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Orange, Miss Clare and Ohotski, Mr Jan and Pyne, Ms Susan and Edwards, Professor Joanne and Doughty, Miss Julie |
| Authors: | Ohotski, J., Long, J.S., Orange, C., Elsberger, B., Doughty, J., Pyne, S., Pyne, N.J., and Edwards, J. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Cancer Sciences |
| Journal Name: | British Journal of Cancer |
| ISSN: | 0007-0920 |
| ISSN (Online): | 1532-1827 |
| Published Online: | 29 March 2012 |
| Related URLs: |
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