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.
Similar content being viewed by others
References
Simstein R, Burow M, Parker A, Weldon C, Beckman B (2003) Apoptosis, chemoresistance, and breast cancer: insights from the MCF-7 cell model system. Exp Biol Med (Maywood) 228:995–1003
Ogretmen B, Hannun YA (2004) Biologically active sphingolipids in cancer pathogenesis and treatment. Nat Rev Cancer 4:604–616
Lavie Y, Cao H, Bursten SL, Giuliano AE, Cabot MC (1996) Accumulation of glucosylceramides in multidrug-resistant cancer cells. J Biol Chem 271:19530–19536
Liu YY, Han TY, Giuliano AE, Cabot MC (2001) Ceramide glycosylation potentiates cellular multidrug resistance. FASEB J 15:719–730
Ogretmen B, Hannun YA (2001) Updates on functions of ceramide in chemotherapy-induced cell death and in multidrug resistance. Drug Resist Updat 4:368–377
Van Brocklyn JR, Young N, Roof R (2003) Sphingosine-1-phosphate stimulates motility and invasiveness of human glioblastoma multiforme cells. Cancer Lett 199:53–60
Nava VE, Hobson JP, Murthy S, Milstien S, Spiegel S (2002) Sphingosine kinase type 1 promotes estrogen-dependent tumorigenesis of breast cancer MCF-7 cells. Exp Cell Res 281:115–127
Struckhoff AP, Bittman R, Burow ME, Clejan S, Elliott S, Hammond T et al (2004) Novel ceramide analogs as potential chemotherapeutic agents in breast cancer. J Pharmacol Exp Ther 309:523–532
French KJ, Upson JJ, Keller SN, Zhuang Y, Yun JK, Smith CD (2006) Antitumor activity of sphingosine kinase inhibitors. J Pharmacol Exp Ther 318:596–603
Cuvillier O (2007) Sphingosine kinase-1-a potential therapeutic target in cancer. Anticancer Drugs 18:105–110
Modlich O, Prisack HB, Munnes M, Audretsch W, Bojar H (2005) Predictors of primary breast cancers responsiveness to preoperative epirubicin/cyclophosphamide-based chemotherapy: translation of microarray data into clinically useful predictive signatures. J Transl Med 3:32
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(9460):671–679
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(38):13550–13555
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(6):R953–R964
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(4):262–272
The International Genomics Consortium (IGC). The expO project (Expression Project For Oncology) http://www.intgen.org/
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(3):203–211
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(11):1665–1671
Zhi L, Leung BP, Melendez AJ (2006) Sphingosine kinase 1 regulates pro-inflammatory responses triggered by TNFalpha in primary human monocytes. J Cell Physiol 208(1):109–115
Olivera A, Urtz N, Mizugishi K, Yamashita Y, Gilfillan AM, Furumoto Y, Gu H, Proia RL, Baumruker T, Rivera J (2006) IgE-dependent activation of sphingosine kinases 1 and 2 and secretion of sphingosine 1-phosphate requires Fyn kinase and contributes to mast cell responses. J Biol Chem 281(5):2515–2525
Taha TA, Mullen TD, Obeid LM (2006) A house divided: ceramide, sphingosine, and sphingosine-1-phosphate in programmed cell death. Biochim Biophys Acta 1758:2027–2036
Berry DA, Cirrincione C, Henderson IC, Citron ML, Budman DR, Goldstein LJ et al (2006) Estrogen-receptor status and outcomes of modern chemotherapy for patients with node-positive breast cancer. JAMA 295:1658–1667
van der Hage JJ, Mieog SJ, van de Vijver M, van de Velde C (2007) Efficacy of adjuvant chemotherapy according to hormone receptor status in young patients with breast cancer: a pooled analysis. Breast Cancer Res 9:R70
Omran OM, Saqr HE, Yates AJ (2006) Molecular mechanisms of GD3-induced apoptosis in U-1242 MG glioma cells. Neurochem Res 31:1171–1180
Zeng G, Gao L, Birkle S, Yu RK (2000) Suppression of ganglioside GD3 expression in a rat F-11 tumor cell line reduces tumor growth, angiogenesis, and vascular endothelial growth factor production. Cancer Res 60:6670–6676
Manka D, Spicer Z, Millhorn DE (2005) Bcl-2/adenovirus E1B 19 kDa interacting protein-3 knockdown enables growth of breast cancer metastases in the lung, liver, and bone. Cancer Res 65:11689–11693
Yang F, Foekens JA, Yu J, Sieuwerts AM, Timmermans M, Klijn JG et al (2006) Laser microdissection and microarray analysis of breast tumors reveal ER-alpha related genes and pathways. Oncogene 25:1413–1419
Liu H, Toman RE, Goparaju SK, Maceyka M, Nava VE, Sankala H et al (2003) Sphingosine kinase type 2 is a putative BH3-only protein that induces apoptosis. J Biol Chem 278:40330–40336
Huwiler A, Zangemeister-Wittke U (2007) Targeting the conversion of ceramide to sphingosine 1-phosphate as a novel strategy for cancer therapy. Crit Rev Oncol Hematol 63:150–159
French KJ, Schrecengost RS, Lee BD, Zhuang Y, Smith SN, Eberly JL et al (2003) Discovery and evaluation of inhibitors of human sphingosine kinase. Cancer Res 63:5962–5969
Kawamori T, Osta W, Johnson KR, Pettus BJ, Bielawski J, Tanaka T et al (2006) Sphingosine kinase 1 is up-regulated in colon carcinogenesis. FASEB J 20:386–388
Van Brooklyn JR, Jackson CA, Pearl DK, Kotur MS, Snyder PJ, Prior TW (2005) Sphingosine kinase-1 expression correlates with poor survival of patients with glioblastoma multiforme: roles of sphingosine kinase isoforms in growth of glioblastoma cell lines. J Neuropathol Exp Neurol 64:695–705
Modok S, Mellor HR, Callaghan R (2006) Modulation of multidrug resistance efflux pump activity to overcome chemoresistance in cancer. Curr Opin Pharmacol 6:350–354
Pilorget A, Demeule M, Barakat S, Marvaldi J, Luis J, Beliveau R (2007) Modulation of P-glycoprotein function by sphingosine kinase-1 in brain endothelial cells. J Neurochem 100:1203–1210
Döll F, Pfeilschifter J, Huwiler A (2005) The epidermal growth factor stimulates sphingosine kinase-1 expression and activity in the human mammary carcinoma cell line MCF7. Biochim Biophys Acta 1738:72–81
Osada M, Yatomi Y, Ohmori T, Ikeda H, Ozaki Y (2002) Enhancement of sphingosine 1-phosphate-induced migration of vascular endothelial cells and smooth muscle cells by an EDG-5 antagonist. Biochem Biophys Res Commun 299:483–487
Acknowledgments
We thank Katherina Kourtis and Samira Adel for expert technical assistance. This work was supported by grants from the Deutsche Krebshilfe, the Margarete Bonifer-Stiftung, Bad Soden, the BANSS-Stiftung, Biedenkopf, and the Dr. Robert Pfleger-Stiftung, Bamberg, and the Deutsche Forschungsgemeinschaft (FG 784/TP5). The efforts of the International Genomics Consortium (IGC) and expO (“expression project for oncology”, http://www.intgen.org/) are gratefully acknowledged.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Ruckhäberle, E., Rody, A., Engels, K. et al. Microarray analysis of altered sphingolipid metabolism reveals prognostic significance of sphingosine kinase 1 in breast cancer. Breast Cancer Res Treat 112, 41–52 (2008). https://doi.org/10.1007/s10549-007-9836-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10549-007-9836-9