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01.11.2008 | Preclinical Study

Microarray analysis of altered sphingolipid metabolism reveals prognostic significance of sphingosine kinase 1 in breast cancer

verfasst von: Eugen Ruckhäberle, Achim Rody, Knut Engels, Regine Gaetje, Gunter von Minckwitz, Susanne Schiffmann, Sabine Grösch, Gerd Geisslinger, Uwe Holtrich, Thomas Karn, Manfred Kaufmann

Erschienen in: Breast Cancer Research and Treatment | Ausgabe 1/2008

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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.

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 4:604–616PubMedCrossRef

Lavie Y, Cao H, Bursten SL, Giuliano AE, Cabot MC (1996) Accumulation of glucosylceramides in multidrug-resistant cancer cells. J Biol Chem 271:19530–19536PubMedCrossRef

Liu YY, Han TY, Giuliano AE, Cabot MC (2001) Ceramide glycosylation potentiates cellular multidrug resistance. FASEB J 15:719–730PubMedCrossRef

Ogretmen B, Hannun YA (2001) Updates on functions of ceramide in chemotherapy-induced cell death and in multidrug resistance. Drug Resist Updat 4:368–377PubMedCrossRef

Van Brocklyn JR, Young N, Roof R (2003) Sphingosine-1-phosphate stimulates motility and invasiveness of human glioblastoma multiforme cells. Cancer Lett 199:53–60PubMedCrossRef

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 281:115–127PubMedCrossRef

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 309:523–532PubMedCrossRef

French KJ, Upson JJ, Keller SN, Zhuang Y, Yun JK, Smith CD (2006) Antitumor activity of sphingosine kinase inhibitors. J Pharmacol Exp Ther 318:596–603PubMedCrossRef

10.

Cuvillier O (2007) Sphingosine kinase-1-a potential therapeutic target in cancer. Anticancer Drugs 18:105–110PubMedCrossRef

11.

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 3:32PubMedCrossRef

12.

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):671–679PubMed

13.

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):13550–13555PubMedCrossRef

14.

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–R964PubMedCrossRef

15.

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):262–272PubMedCrossRef

16.

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

17.

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):203–211PubMedCrossRef

18.

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):1665–1671PubMedCrossRef

19.

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):109–115PubMedCrossRef

20.

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):2515–2525PubMedCrossRef

21.

Taha TA, Mullen TD, Obeid LM (2006) A house divided: ceramide, sphingosine, and sphingosine-1-phosphate in programmed cell death. Biochim Biophys Acta 1758:2027–2036PubMedCrossRef

22.

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 295:1658–1667PubMedCrossRef

23.

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:R70PubMedCrossRef

24.

Omran OM, Saqr HE, Yates AJ (2006) Molecular mechanisms of GD3-induced apoptosis in U-1242 MG glioma cells. Neurochem Res 31:1171–1180PubMedCrossRef

25.

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 60:6670–6676PubMed

26.

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 65:11689–11693PubMedCrossRef

27.

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 25:1413–1419PubMedCrossRef

28.

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 278:40330–40336PubMedCrossRef

29.

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 63:150–159PubMedCrossRef

30.

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 63:5962–5969PubMed

31.

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 20:386–388PubMed

32.

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 64:695–705CrossRef

33.

Modok S, Mellor HR, Callaghan R (2006) Modulation of multidrug resistance efflux pump activity to overcome chemoresistance in cancer. Curr Opin Pharmacol 6:350–354PubMedCrossRef

34.

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 100:1203–1210PubMedCrossRef

35.

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 1738:72–81PubMed

36.

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 299:483–487PubMedCrossRef

Titel: Microarray analysis of altered sphingolipid metabolism reveals prognostic significance of sphingosine kinase 1 in breast cancer
verfasst von: Eugen Ruckhäberle
Achim Rody
Knut Engels
Regine Gaetje
Gunter von Minckwitz
Susanne Schiffmann
Sabine Grösch
Gerd Geisslinger
Uwe Holtrich
Thomas Karn
Manfred Kaufmann
Publikationsdatum: 01.11.2008
Verlag: Springer US
Erschienen in: Breast Cancer Research and Treatment / Ausgabe 1/2008
Print ISSN: 0167-6806
Elektronische ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-007-9836-9

Springer Medizin

Microarray analysis of altered sphingolipid metabolism reveals prognostic significance of sphingosine kinase 1 in breast cancer

Abstract

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Springer Medizin

Abstract

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