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Carcinogenesis Advance Access originally published online on March 11, 2009
Carcinogenesis 2009 30(5):745-752; 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 Schiffmann*,{dagger}, Jessica Sandner{dagger}, Kerstin Birod, Ivonne Wobst, Carlo Angioni, Eugen Ruckhäberle1, Manfred Kaufmann1, Hanns Ackermann2, Jörn Lötsch, Helmut Schmidt, Gerd Geisslinger and Sabine Grösch

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

* To whom correspondence should be addressed. Tel: +49 69 6301 7820; Fax: +49 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 coupled with tandem mass spectrometry (LC-MS/MS). The total ceramide levels in malignant tumor tissue samples were statistically significantly elevated when compared with 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 with benign and normal tissue. The augmentation of the various ceramides could be assigned to an increase of the messenger RNA levels of ceramide synthases (CerS) LASS2 (longevity assurance), 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 with ER negative tumor tissues. In conclusion, progression in breast cancer is associated with increased ceramide levels due to an upregulation of specific LASS genes.

Abbreviations: Cer, ceramide; CerS, (dihydro)ceramide synthase; dhCer, dihydroceramide; dhSph, sphinganine; ER, estrogen receptor; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; LASS, longevity assurance homolog; LN, lymph node; mRNA, messenger RNA; S1P, sphingosine-1-phosphate; Sph, sphingosine; SphK, sphingosine kinase; SPT, L-serine palmitoyl-CoA transferase; SPTLC, L-serine palmitoyl-CoA transferase long chain

{dagger} These authors contributed equally to this work.

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


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