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

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, S1P(1), S1P(2), and S1P(3)), SK1, and ERK-1/2 expression levels. Expression levels of both SKI and ERK-1/2 were already available for the cohort, and S1P(1), S1P(2), and S1P(3) levels were established by immunohistochemical analysis. High membrane S1P(1) expression was associated with shorter time to recurrence (P = 0.008). High cytoplasmic S1P(1) and S1P(3) 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 S1P(1) and cytoplasmic ERK-1/2 expression levels (P = 0.004) and high cytoplasmic S1P(3) 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, S1P(1) and/or S1P(3) and ERK-1/2 might drive breast cancer progression, and these findings, therefore, warrant further investigation. (Am J Pathol 2010, 177:2205-2215; DOI: 10.2353/ajpath.2010.100220)