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Carcinogenesis Advance Access published online on March 11, 2009
Carcinogenesis, doi:10.1093/carcin/bgp061
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© The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Ceramide synthases and ceramide levels are increased in breast cancer tissue

Susanne Schiffmann1,*, Jessica Sandner1,*, Kerstin Birod1, Ivonne Wobst1, Carlo Angioni1, Eugen Ruckhäberle2, Manfred Kaufmann2, Hanns Ackermann3, Jörn Lötsch1, Helmut Schmidt1, Gerd Geisslinger1 and Sabine Grösch1

1 pharmazentrum frankfurt/ZAFES, Institute of Clinical Pharmacology, Goethe-University, Theodor-Stern-Kai 7, 60590 Frankfurt/Main, Germany
2 Department of Gynecology, Goethe-University, 60590 Frankfurt/Main, Germany
3 Institute of Biomathematics, Goethe-University, 60590 Frankfurt/Main, Germany

Corresponding author: Susanne Schiffmann, PhD, Institute of Clinical Pharmacology Goethe-University, Theodor-Stern-Kai 7, 60590 Frankfurt/Main, Germany, Tel.: 0049/69-6301 7820, Fax: 0049/69-6301 7636, Email: Susanne.schiffmann{at}med.uni-frankfurt.de

Several in vitro studies have correlated dysfunction of the sphingolipid signaling pathway with promotion of tumor cell growth as well as progression and resistance of tumors to chemotherapeutic agents. As ceramides (Cer) constitute the structural backbones of all sphingolipids we investigated the endogenous ceramide levels in 43 malignant breast tumors and 21 benign breast biopsies and compared them with those of normal tissues using liquid chromatography tandem mass spectrometry (LC-MS/MS). The total ceramide levels in malignant tumor tissue samples were statistically significantly elevated when compared to normal tissue samples. Upregulation of the total ceramide level averaged 12-fold and 4-fold higher than normal tissue samples, for malignant tumors and benign tissues, respectively. Specifically, the levels of C16:0-Cer, C24:1-Cer and C24:0-Cer were significantly raised in malignant tumors as compared to benign and normal tissue. The augmentation of the various ceramides could be assigned to an increase of the mRNA levels of ceramide synthases (CerS) LASS2 (LAG1 longevity assurance homolog), LASS4 and LASS6. Notably, elevated levels of C16:0-Cer were associated with a positive lymph node status, indicating a metastatic potential for this ceramide. Moreover, the levels of C18:0-Cer and C20:0-Cer were significantly higher in estrogen receptor (ER) positive tumor tissues as compared to ER negative tumor tissues. In conclusion, progression in breast cancer is associated with increased ceramide levels due to an up-regulation of specific LASS genes.

Key Words: breast cancer • ceramide • dihydro(ceramide) synthase • LC-MS/MS

* Authors contributed equally

Received October 28, 2008; revised February 12, 2009; accepted March 7, 2009.


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