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01-11-2008 | Preclinical Study

Microarray analysis of altered sphingolipid metabolism reveals prognostic significance of sphingosine kinase 1 in breast cancer

Authors: Eugen Ruckhäberle, Achim Rody, Knut Engels, Regine Gaetje, Gunter von Minckwitz, Susanne Schiffmann, Sabine Grösch, Gerd Geisslinger, Uwe Holtrich, Thomas Karn, Manfred Kaufmann

Published in: Breast Cancer Research and Treatment | Issue 1/2008

Abstract

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.

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Title: Microarray analysis of altered sphingolipid metabolism reveals prognostic significance of sphingosine kinase 1 in breast cancer
Authors: Eugen Ruckhäberle
Achim Rody
Knut Engels
Regine Gaetje
Gunter von Minckwitz
Susanne Schiffmann
Sabine Grösch
Gerd Geisslinger
Uwe Holtrich
Thomas Karn
Manfred Kaufmann
Publication date: 01-11-2008
Publisher: Springer US
Published in: Breast Cancer Research and Treatment / Issue 1/2008
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-007-9836-9

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