High expression of sphingosine 1-phosphate receptors, S1P1 and S1P3, sphingosine kinase 1, and extracellular signal-regulated kinase-1/2 is associated with development of tamoxifen resistance in estrogen receptor-positive breast cancer patients

Watson, C., Long, J.S., Orange, C., Tannahill, C.L., Mallon, E., McGlynn, L.M., Pyne, S., Pyne, N.J. and Edwards, J. (2010) High expression of sphingosine 1-phosphate receptors, S1P1 and S1P3, sphingosine kinase 1, and extracellular signal-regulated kinase-1/2 is associated with development of tamoxifen resistance in estrogen receptor-positive breast cancer patients. American Journal of Pathology, 177(5), pp. 2205-2215. (doi: 10.2353/ajpath.2010.100220)

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Abstract

Various studies in cell lines have previously demonstrated that sphingosine kinase 1 (SK1) and extracellular signal-regulated kinase 1/2 (ERK-1/2) interact in an estrogen receptor (ER)-dependent manner to influence both breast cancer cell growth and migration. A cohort of 304 ER-positive breast cancer patients was used to investigate the prognostic significance of sphingosine 1-phosphate (S1P) receptors 1, 2, and 3 (ie, S1P1, S1P2, and S1P3), SK1, and ERK-1/2 expression levels. Expression levels of both SK1 and ERK-1/2 were already available for the cohort, and S1P1, S1P2, and S1P3 levels were established by immunohistochemical analysis. High membrane S1P1 expression was associated with shorter time to recurrence (P = 0.008). High cytoplasmic S1P1 and S1P3 expression levels were also associated with shorter disease-specific survival times (P = 0.036 and P = 0.019, respectively). Those patients with tumors that expressed high levels of both cytoplasmic SK1 and ERK-1/2 had significantly shorter recurrence times than those that expressed low levels of cytoplasmic SK1 and cytoplasmic ERK-1/2 (P = 0.00008), with a difference in recurrence time of 10.5 years. Similarly, high cytoplasmic S1P1 and cytoplasmic ERK-1/2 expression levels (P = 0.004) and high cytoplasmic S1P3 expression and cytoplasmic ERK-1/2 expression levels (P = 0.004) were associated with shorter recurrence times. These results support a model in which the interaction between SK1, S1P1, and/or S1P3 and ERK-1/2 might drive breast cancer progression, and these findings, therefore, warrant further investigation.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Tannahill, Ms Claire and McGlynn, Dr Liane and Edwards, Professor Joanne and Watson, Dr Carol
Authors: Watson, C., Long, J.S., Orange, C., Tannahill, C.L., Mallon, E., McGlynn, L.M., Pyne, S., Pyne, N.J., and Edwards, J.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:American Journal of Pathology
Publisher:American Society for Investigative Pathology
ISSN:0002-9440
ISSN (Online):1525-2191

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