title: Ceramide synthases and ceramide levels are increased in breast cancer tissue.
abstract: 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 C(16:0)-Cer, C(24:1)-Cer and C(24:0)-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 C(16:0)-Cer were associated with a positive lymph node status, indicating a metastatic potential for this ceramide. Moreover, the levels of C(18:0)-Cer and C(20:0)-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.
authors.affiliation: pharmazentrum frankfurt/ZAFES, Institute of Clinical Pharmacology, 60590 Frankfurt am Main, Germany. susanne.schiffmann@med.uni-frankfurt.de
authors.forename: Susanne
authors.initials: S
authors.lastname: Schiffmann
authors.forename: Jessica
authors.initials: J
authors.lastname: Sandner
authors.forename: Kerstin
authors.initials: K
authors.lastname: Birod
authors.forename: Ivonne
authors.initials: I
authors.lastname: Wobst
authors.forename: Carlo
authors.initials: C
authors.lastname: Angioni
authors.forename: Eugen
authors.initials: E
authors.lastname: Ruckhäberle
authors.forename: Manfred
authors.initials: M
authors.lastname: Kaufmann
authors.forename: Hanns
authors.initials: H
authors.lastname: Ackermann
authors.forename: Jörn
authors.initials: J
authors.lastname: Lötsch
authors.forename: Helmut
authors.initials: H
authors.lastname: Schmidt
authors.forename: Gerd
authors.initials: G
authors.lastname: Geisslinger
authors.forename: Sabine
authors.initials: S
authors.lastname: Grösch
mesh_terms: D001940:Breast / Q000201:enzymology / Q000378:metabolism; D001941:Breast Diseases / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002455:Cell Division; D002518:Ceramides / Q000378:metabolism*; D005260:Female; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics; D010088:Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D011960:Receptors, Estrogen / Q000378:metabolism; D012016:Reference Values; D013107:Sphingolipids / Q000378:metabolism; D051049:Sphingosine N-Acyltransferase; D015854:Up-Regulation
chemical_list: D002518:Ceramides; D008565:Membrane Proteins; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D013107:Sphingolipids; D010088:Oxidoreductases; C108138:dihydroceramide desaturase; C506123:CERS6 protein, human; D051049:Sphingosine N-Acyltransferase