Skip to main content

Advertisement

SpringerLink
Log in

Gene expression of ceramide kinase, galactosyl ceramide synthase and ganglioside GD3 synthase is associated with prognosis in breast cancer

  • Original Paper
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

Abstract

Purpose

Sphingolipids are bioactive lipids implicated in apoptosis, cell survival and proliferation. We analyzed the prognostic value of enzymes from sphingolipid metabolism in breast cancer.

Methods

Differences in expression of ceramide galactosyl transferase (UGT8), ceramide kinase (CERK), and Ganglioside GD3-Synthase (ST8SIA1) in breast cancer cells were investigated by using microarray data of 1,581 tumor samples.

Results

UGT8, CERK, and ST8SIA1 were associated with poor pathohistological grading (P < 0.001). High CERK expression was correlated with ErbB2 status (P = 0.006). Among ER positive breast cancers a significant worse prognosis for patients with tumors showing low ST8SIA1 and UGT8 expression was observed. In the ER negative subgroup those samples with high CERK expression displayed a worse prognosis. In a multivariate analysis only ST8SIA1 and tumor size remained significant.

Conclusions

Our experiments reveal that expression of enzymes from the sphingolipid metabolism has prognostic implications in breast cancer.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Ahr A, Karn T, Solbach C, Seiter T, Strebhardt K, Holtrich U, Kaufmann M (2002) Identification of high risk breast-cancer patients by gene expression profiling. Lancet 359:131–132. doi:10.1016/S0140-6736(02)07337-3

    Article  PubMed  Google Scholar 

  • Alexe G, Dalgin GS, Scanfeld D, Tamayo P, Mesirov JP, DeLisi C, Harris L, Barnard N, Martel M, Levine AJ, Ganesan S, Bhanot G (2007) High expression of lymphocyte-associated genes in node-negative HER2 + breast cancers correlates with lower recurrence rates. Cancer Res 67:10669–10676. doi:10.1158/0008-5472.CAN-07-0539

    Article  PubMed  CAS  Google Scholar 

  • Bonnefoi H, Potti A, Delorenzi M, Mauriac L, Campone M, Tubiana-Hulin M, Petit T, Rouanet P, Jassem J, Blot E, Becette V, Farmer P, André S, Acharya CR, Mukherjee S, Cameron D, Bergh J, Nevins JR, Iggo RD (2007) Validation of gene signatures that predict the response of breast cancer to neoadjuvant chemotherapy: a substudy of the EORTC 10994/BIG 00–01 clinical trial. Lancet Oncol 8:1071–1078. doi:10.1016/S1470-2045(07)70345-5

    Article  PubMed  CAS  Google Scholar 

  • Dahm F, Bielawska A, Nocito A, Georgiev P, Szulc ZM, Bielawski J, Jochum W, Dindo D, Hannun YA, Clavien PA (2008) Mitochondrially targeted ceramide LCL-30 inhibits colorectal cancer in mice. Br J Cancer 98(1):98–105

    Google Scholar 

  • Desmedt C, Piette F, Loi S, Wang Y, Lallemand F, Haibe-Kains B, Viale G, Delorenzi M, Zhang Y, d’Assignies MS, Bergh J, Lidereau R, Ellis P, Harris AL, Klijn JG, Foekens JA, Cardoso F, Piccart MJ, Buyse M, Sotiriou C (2007) TRANSBIG Consortium. (2007) Strong time dependence of the 76-gene prognostic signature for node-negative breast cancer patients in the TRANSBIG multicenter independent validation series. Clin Cancer Res 13:3207–3214

    Article  PubMed  CAS  Google Scholar 

  • Devalapally H, Duan Z, Seiden MV, Amiji MM (2007) Paclitaxel and ceramide co-administration in biodegradable polymeric nanoparticulate delivery system to overcome drug resistance in ovarian cancer. Int J Cancer 121(8):1830–1838. doi:10.1002/ijc.22886

    Article  PubMed  CAS  Google Scholar 

  • Foekens JA, Atkins D, Zhang Y, Sweep FC, Harbeck N, Paradiso A, Cufer T, Sieuwerts AM, Talantov D, Span PN, Tjan-Heijnen VC, Zito AF, Specht K, Hoefler H, Golouh R, Schittulli F, Schmitt M, Beex LV, Klijn JG, Wang Y (2006) Multicenter validation of a gene expression-based prognostic signature in lymph node-negative primary breast cancer. J Clin Oncol 24:1665–1671. doi:10.1200/JCO.2005.03.9115

    Article  PubMed  CAS  Google Scholar 

  • Fujii S, Shimizu K, Hemmi H, Fukui M, Bonito AJ, Chen G, Franck RW, Tsuji M, Steinman RM (2006) Glycolipid alpha-C-galactosylceramide is a distinct inducer of dendritic cell function during innate and adaptive immune responses of mice. Proc Natl Acad Sci USA 103(30):11252–11257 (Epub 2006 Jul 14)

    Google Scholar 

  • Giaccone G, Punt CJA, Ando Y et al (2002) A phase I study of the natural killer T-cell ligand a-galactosylceramide (KRN7000) in patients with solid tumors. Clin Cancer Res 8:3702–3709

    PubMed  CAS  Google Scholar 

  • Godfrey DI, Kronenberg M (2004) Going both ways: immune regulation via CD1d-dependent NKT cells. J Clin Invest 114:1379–1388

    PubMed  CAS  Google Scholar 

  • Gomez-Munoz A (2006) Ceramide 1-phosphate/ceramide, a switch between life and death. Biochim Biophys Acta 1758:2049–2056. doi:10.1016/j.bbamem.2006.05.011

    Article  PubMed  CAS  Google Scholar 

  • Gomez-Munoz A, Duffy PA, Martin A, O’Brien L, Byun H-S, Bittman R, Brindley DN (1995) Short-chain ceramide-1-phosphates are novel stimulators of DNA synthesis and cell division: antagonism by cell-permeable ceramides. Mol Pharmacol 47:883–889

    CAS  Google Scholar 

  • Gomez-Munoz A, Kong JY, Salh B, Steinbrecher UP (2004) Ceramide-1-phosphate blocks apoptosis through inhibition of acid sphingomyelinase in macrophages. J Lipid Res 45:99–105. doi:10.1194/jlr.M300158-JLR200

    Article  PubMed  CAS  Google Scholar 

  • Gong Y, Yan K, Lin F, Anderson K, Sotiriou C, Andre F, Holmes FA, Valero V, Booser D, Pippen JE Jr, Vukelja S, Gomez H, Mejia J, Barajas LJ, Hess KR, Sneige N, Hortobagyi GN, Pusztai L, Symmans WF (2007) Determination of oestrogen-receptor status and ERBB2 status of breast carcinoma: a gene-expression profiling study. Lancet Oncol 8:203–211. doi:10.1016/S1470-2045(07)70042-6

    Article  PubMed  CAS  Google Scholar 

  • Gouaze V, Liu YY, Prickett CS, Yu JY, Giuliano AE, Cabot MC (2005) Glucosylceramide synthase blockade down-regulates P-glycoprotein and resensitizes multidrug-resistant breast cancer cells to anticancer drugs. Cancer Res 65(9):3861–3867. doi:10.1158/0008-5472.CAN-04-2329

    Article  PubMed  CAS  Google Scholar 

  • Gouaze-Andersson V, Cabot MC (2006) Glycosphingolipids and drug resistance. Biochim Biophys Acta 1758:2096–2103. doi:10.1016/j.bbamem.2006.08.012

    Article  PubMed  CAS  Google Scholar 

  • Gouaze-Andersson V, Yu JY, Kreitenberg AJ, Bielawska A, Giuliano AE, Cabot MC (2007) Ceramide and glucosylceramide upregulate expression of the multidrug resistance gene MDR1 in cancer cells. Biochim Biophys Acta 1771(12):1407–1417

    PubMed  CAS  Google Scholar 

  • Hannun YA, Obeid LM (2008) Principles of bioactive lipid signaling: lessons from sphingolipids. Nat Rev Mol Cell Biol 9:139–150. doi:10.1038/nrm2329

    Article  PubMed  CAS  Google Scholar 

  • Hattori T, Kokura S, Okuda T, Okayama T, Takagi T, Handa O, Naito Y, Yoshida N, Yoshikawa T (2007) Antitumor effect of whole body hyperthermia with alpha-galactosylceramide in a subcutaneous tumor model of colon cancer. Int J Hyperthermia 23(7):591–598. doi:10.1080/02656730701708328

    Article  PubMed  CAS  Google Scholar 

  • Hayakawa Y, Takeda K, Yagita H, Smyth MJ, Van Kaer L, Okumura K, Saiki I (2002) IFN-gamma-mediated inhibition of tumor angiogenesis by natural killer T-cell ligand, alpha-galactosylceramide. Blood 100(5):1728–1733

    PubMed  CAS  Google Scholar 

  • Hinkovska-Galcheva V, Boxer LA, Kindzelskii A, Hiraoka M, Abe A, Goparju S, Spiegel S, Petty HR, Shayman JA (2005) Ceramide 1-phosphate, a mediator of phagocytosis. J Biol Chem 280:26612–26621. doi:10.1074/jbc.M501359200

    Article  PubMed  CAS  Google Scholar 

  • Huwiler A, Kolter T, Pfeilschifter J, Sandhoff K (2000) Physiology and pathophysiology of sphingolipid metabolism and signaling. Biochim Biophys Acta 1485(2–3):63–99

    PubMed  CAS  Google Scholar 

  • Huwiler A, Pfeilschifter J (2006) Altering the sphingosine-1-phosphate/ceramide balance: a promising approach for tumor therapy. Curr Pharm Des 12(35):4625–4635. doi:10.2174/138161206779010422

    Article  PubMed  CAS  Google Scholar 

  • Irizarry RA, Bolstad BM, Collin F, Cope LM, Hobbs B, Speed TP (2003) Summaries of Affymetrix GeneChip probe level data. Nucleic Acids Res 31:e15. doi:10.1093/nar/gng015

    Article  PubMed  CAS  Google Scholar 

  • Ishikawa A, Motohashi S, Ishikawa E et al (2005) A phase I study of a-galactosylceramide (KRN7000)-pulsed dendritic cells in patients with advanced and recurrent non-small cell lung cancer. Clin Cancer Res 11:1910–1917. doi:10.1158/1078-0432.CCR-04-1453

    Article  PubMed  CAS  Google Scholar 

  • Ko K, Furukawa K, Takahashi T, Urano T, Sanai Y, Nagino M, Nimura Y, Furukawa K (2006) Fundamental study of small interfering RNAs for ganglioside GD3 synthase gene as a therapeutic target of lung cancers. Oncogene 25(52):6924–6935. doi:10.1038/sj.onc.1209683

    Article  PubMed  CAS  Google Scholar 

  • Lahiri S, Futerman AH (2007) The metabolism and function of sphingolipids and glycosphingolipids. Cell Mol Life Sci 64(17):2270–2284. doi:10.1007/s00018-007-7076-0

    Article  PubMed  CAS  Google Scholar 

  • Lamour NF, Chalfant CE (2008) Ceramide kinase and the ceramide-1-phosphate/cPLA2alpha interaction as a therapeutic target. Curr Drug Targets 9(8):674–682. doi:10.2174/138945008785132349

    Article  PubMed  CAS  Google Scholar 

  • Li C, Wong WH (2001) Model-based analysis of oligonucleotide arrays: expression index computation and outlier detection. Proc Natl Acad Sci USA 98(1):31–36. doi:10.1073/pnas.011404098

    Article  PubMed  CAS  Google Scholar 

  • Liu YY, Yu JY, Yin D, Patwardhan GA, Gupta V, Hirabayashi Y, Holleran WM, Giuliano AE, Jazwinski SM, Gouaze-Andersson V, Consoli DP, Cabot MC (2008) A role for ceramide in driving cancer cell resistance to doxorubicin. FASEB J 22(7):2541–2551. doi:10.1096/fj.07-092981

    Article  PubMed  CAS  Google Scholar 

  • Liu K, Idoyaga J, Charalambous A, Fujii S, Bonito A, Mordoh J, Wainstok R, Bai XF, Liu Y, Steinman RMJ (2005) Innate NKT lymphocytes confer superior adaptive immunity via tumor-capturing dendritic cells. Exp Med 202:1507–1516. doi:10.1084/jem.20050956

    Article  CAS  Google Scholar 

  • Loi S, Haibe-Kains B, Desmedt C, Lallemand F, Tutt AM, Gillet C, Ellis P, Harris A, Bergh J, Foekens JA, Klijn JG, Larsimont D, Buyse M, Bontempi G, Delorenzi M, Piccart MJ, Sotiriou C (2007) Definition of clinically distinct molecular subtypes in estrogen receptor-positive breast carcinomas through genomic grade. J Clin Oncol 25:1239–1246. doi:10.1200/JCO.2006.07.1522

    Article  PubMed  CAS  Google Scholar 

  • Miller LD, Smeds J, George J, Vega VB, Vergara L, Ploner A, Pawitan Y, Hall P, Klaar S, Liu ET, Bergh J (2005) An expression signature for p53 status in human breast cancer predicts mutation status, transcriptional effects, and patient survival. Proc Natl Acad Sci USA 102:13550–13555. doi:10.1073/pnas.0506230102

    Article  PubMed  CAS  Google Scholar 

  • Minn AJ, Gupta GP, Padua D, Bos P, Nguyen DX, Nuyten D, Kreike B, Zhang Y, Wang Y, Ishwaran H, Foekens JA, van de Vijver M, Massagué J (2007) Lung metastasis genes couple breast tumor size and metastatic spread. Proc Natl Acad Sci USA 104:6740–6745. doi:10.1073/pnas.0701138104

    Article  PubMed  CAS  Google Scholar 

  • Minn AJ, Gupta GP, Siegel PM, Bos PD, Shu W, Giri DD, Viale A, Olshen AB, Gerald WL, Massagué J (2005) Genes that mediate breast cancer metastasis to lung. Nature 436:518–524. doi:10.1038/nature03799

    Article  PubMed  CAS  Google Scholar 

  • Mitra P, Maceyka M, Payne SG, Lamour N, Milstien S, Chalfant CE, Spiegel S (2007) Ceramide kinase regulates growth and survival of A549 human lung adenocarcinoma cells. FEBS Lett 581(4):735–740 (Epub 2007 Jan 25)

    Google Scholar 

  • Mitsutake S, Kim TJ, Inagaki Y, Kato M, Yamashita T, Igarashi Y (2004) Ceramide kinase is a mediator of calcium-dependent degranulation in mast cells. J Biol Chem 279:17570–17577. doi:10.1074/jbc.M312885200

    Article  PubMed  CAS  Google Scholar 

  • Modrak DE, Gold DV, Goldenberg DM (2006) Sphingolipid targets in cancer therapy. Mol Cancer Ther 5(2):200–208. doi:10.1158/1535-7163.MCT-05-0420

    Article  PubMed  CAS  Google Scholar 

  • Motohashi S, Ishikawa A, Ishikawa E et al (2006) A phase I study of in vitro expanded natural killer T cells inpatients with advanced and recurrent non-small cell lung cancer. Clin Cancer Res 12:6079–6086. doi:10.1158/1078-0432.CCR-06-0114

    Article  PubMed  CAS  Google Scholar 

  • Park JE, Wu DY, Prendes M, Lu SX, Ragupathi G, Schrantz N, Chapman PB (2008) Fine specificity of natural killer T cells against GD3 ganglioside and identification of GM3 as an inhibitory natural killer T-cell ligand. Immunology 123(1):145–155. doi:10.1111/j.1365-2567.2007.02760.x

    Article  PubMed  CAS  Google Scholar 

  • Pawitan Y, Bjohle J, Amler L, Borg AL, Egyhazi S, Hall P, Han X, Holmberg L, Huang F, Klaar S, Liu ET, Miller L, Nordgren H, Ploner A, Sandelin K, Shaw PM, Smeds J, Skoog L, Wedren S, Bergh J (2005) Gene expression profiling spares early breast cancer patients from adjuvant therapy: derived and validated in two population-based cohorts. Breast Cancer Res 7:R953–R964. doi:10.1186/bcr1325

    Article  PubMed  CAS  Google Scholar 

  • Rody A, Holtrich U, Gaetje R, Gehrmann M, Engels K, von Minckwitz G, Loibl S, Diallo-Danebrock R, Ruckhäberle E, Metzler D, Ahr A, Solbach C, Karn T, Kaufmann M (2007) Poor outcome in estrogen receptor-positive breast cancers predicted by loss of plexin B1. Clin Cancer Res 13:1115–1122. doi:10.1158/1078-0432.CCR-06-2433

    Article  PubMed  CAS  Google Scholar 

  • Ruckhäberle E, Karn T, Hanker L, Gätje R, Metzler D, Holtrich U, Kaufmann M, Rody A (2008) Prognostic relevance of glucosylceramide synthase (GCS) expression in breast cancer. J Cancer Res Clin Oncol 135(1):81–90

    Article  PubMed  CAS  Google Scholar 

  • Ruckhäberle E, Rody A, Engels K, Gaetje R, von Minckwitz G, Schiffmann S, Grosch S, Geisslinger G, Holtrich U, Karn T, Kaufmann M (2007) Microarray analysis of altered sphingolipid metabolism reveals prognostic significance of sphingosine kinase 1 in breast cancer. Breast Cancer Res Treat 112(1):41–52

    Article  PubMed  CAS  Google Scholar 

  • Saxena S, Banerjee M, Shirumalla RK, Ray A (2008) Ceramide kinase: a potential anti-inflammatory target? Curr Opin Investig Drugs 9(5):455–462

    PubMed  CAS  Google Scholar 

  • Shida D, Takabe K, Kapitonov D, Milstien S, Spiegel S (2008) Targeting SphK1 as a new strategy against cancer. Curr Drug Targets 9(8):662–673. doi:10.2174/138945008785132402

    Article  PubMed  CAS  Google Scholar 

  • Sotiriou C, Wirapati P, Loi S, Harris A, Fox S, Smeds J, Nordgren H, Farmer P, Praz V, Haibe-Kains B, Desmedt C, Larsimont D, Cardoso F, Peterse H, Nuyten D, Buyse M, Van de Vijver MJ, Bergh J, Piccart M, Delorenzi M (2006) Gene expression profiling in breast cancer: understanding the molecular basis of histologic grade to improve prognosis. J Natl Cancer Inst 98:262–272

    Article  PubMed  CAS  Google Scholar 

  • Struckhoff AP, Bittman R, Burow ME, Clejan S, Elliott S, Hammond T, Tang Y, Beckman BS (2004) Novel ceramide analogs as potential chemotherapeutic agents in breast cancer. J Pharmacol Exp Ther 309(2):523–532

    Article  PubMed  CAS  Google Scholar 

  • Taha TA, Mullen TD, Obeid LM (2006) A house divided: ceramidesphingosine, and sphingosine-1-phosphate in programmed cell death. Biochim Biophys Acta 1758:2027–2036. doi:10.1016/j.bbamem.2006.10.018

    Article  PubMed  CAS  Google Scholar 

  • Takabe K, Paugh SW, Milstien S, Spiegel S (2008) “Inside-out” signaling of sphingosine-1-phosphate: therapeutic targets. Pharmacol Rev 60(2):181–195. doi:10.1124/pr.107.07113

    Article  PubMed  CAS  Google Scholar 

  • Teng MW, Westwood JA, Darcy PK, Sharkey J, Tsuji M, Franck RW, Porcelli SA, Besra GS, Takeda K, Yagita H, Kershaw MH, Smyth MJ (2007) Combined natural killer T-cell based immunotherapy eradicates established tumors in mice. Cancer Res 67(15):7495–7504. doi:10.1158/0008-5472.CAN-07-0941

    Article  PubMed  CAS  Google Scholar 

  • The International Genomics Consortium (IGC) The expO project (Expression Project For Oncology) http://www.intgen.org/

  • Uchida T, Horiguchi S, Tanaka Y, Yamamoto H, Kunii N, Motohashi S, Taniguchi M, Nakayama T, Okamoto Y (2008) Phase I study of alpha-galactosylceramide-pulsed antigen presenting cells administration to the nasal submucosa in unresectable or recurrent head and neck cancer. Cancer Immunol Immunother 57(3):337–345. doi:10.1007/s00262-007-0373-5

    Article  PubMed  CAS  Google Scholar 

  • Visentin B, Vekich JA, Sibbald BJ, Cavalli AL, Moreno KM, Matteo RG, Garland WA, Lu Y, Yu S, Hall HS, Kundra V, Mills GB, Sabbadini RA (2006) Validation of an anti-sphingosine-1-phosphate antibody as a potential therapeutic in reducing growth, invasion, and angiogenesis in multiple tumor lineages. Cancer Cell 9(3):225–238. doi:10.1016/j.ccr.2006.02.023

    Article  PubMed  CAS  Google Scholar 

  • Wang Y, Klijn JG, Zhang Y, Sieuwerts AM, Look MP, Yang F, Talantov D, Timmermans M, Meijer-van Gelder ME, Yu J, Jatkoe T, Berns EM, Atkins D, Foekens JA (2005) Gene-expression profiles to predict distant metastasis of lymph-node-negative primary breast cancer. Lancet 365:671–679

    PubMed  CAS  Google Scholar 

  • Wu DY, Segal NH, Sidobre S, Kronenberg M, Chapman PB (2003) Cross-presentation of disialoganglioside GD3 to natural killer T cells. J Exp Med 198:173–181. doi:10.1084/jem.20030446

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank Samira Adel and Katherina Kourtis for expert technical assistance. This work was supported by grants from the Deutsche Krebshilfe, the Margarete Bonifer-Stiftung, Bad Soden, the Dr. Robert Pfleger-Stiftung, Bamberg, and the BANSS-Stiftung, Biedenkopf. Tissue samples of breast cancer cases of the University of Frankfurt were obtained with informed consent and approval of the institutional review board of the University of Frankfurt.

Conflict of interest statement

There are no conflicts of interest to declare.

Author information

Authors and Affiliations

  1. Department of Obstetrics and Gynecology, J. W. Goethe-University, Theodor-Stern-Kai 7, 60590, Frankfurt, Germany

    Eugen Ruckhäberle, Thomas Karn, Achim Rody, Lars Hanker, Regine Gätje, Uwe Holtrich & Manfred Kaufmann

  2. Department of Computer Science and Mathematics, J. W. Goethe-University, Frankfurt, Germany

    Dirk Metzler

Authors
  1. Eugen Ruckhäberle
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Thomas Karn
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Achim Rody
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lars Hanker
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Regine Gätje
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Dirk Metzler
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Uwe Holtrich
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Manfred Kaufmann
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Eugen Ruckhäberle.

Additional information

E. Ruckhäberle and T. Karn contributed equally to this manuscript.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ruckhäberle, E., Karn, T., Rody, A. et al. Gene expression of ceramide kinase, galactosyl ceramide synthase and ganglioside GD3 synthase is associated with prognosis in breast cancer. J Cancer Res Clin Oncol 135, 1005–1013 (2009). https://doi.org/10.1007/s00432-008-0536-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00432-008-0536-6

Keywords

Search

Navigation