Beside their structural role for the cell membrane the family of
sphingolipids act as effector molecules in signal transduction with links to various aspects of
cancer initiation, progression and treatment response. The "
sphingolipid rheostat" balances between apoptosis inducing ceramid and growth promoting
sphingosine-1-phosphate. We analyzed gene expression of 43
proteins from this pathway in different subtypes of
breast cancer using microarray data of 1,269
tumor samples (test set n=171; validation sets n=1098) and observed significant differences for several genes.
Sphingosine kinase 1 (SPHK1),
ceramide galactosyltransferase (UGT8), and
Ganglioside GD3-Synthase (ST8SIA1) displayed higher expression among ER negative
tumors. In contrast, glucosylceramidsynthase (GCS), dihydroceramidsynthases (LASS4, LASS 6) and
acid ceramidase (ASAH1) were higher expressed in ER positive samples. Survival analysis revealed a worse outcome of patients with high SPHK1 expression. To avoid a confounding effect of the ER status we also restricted the analysis to 750 patients with ER positive
tumors. Again a worse outcome was observed for
tumors displaying high SPHK1 expression. While 75.8+/-1.9% of the patients with
tumors low in SPHK1 expression were free of
metastasis at 5 years, this was the case for only 64.9+/-3.6% of patients with
tumors displaying high SPHK1 expression (P=0.008). Immunohistochemistry identified the
carcinoma cells as the major source of SPHK1 expression in the
tumor. The correlation of SPHK1 with a poor prognosis as well as its high expression among ER negative
tumors are in line with the antiapoptotic and proliferative properties of its product
sphingosine-1-phosphate. Targeting of the
sphingolipid rheostat may thus open new treatment options.