Top

Journal of Cancer Research and Clinical Oncology

Published in:

01-01-2009 | Original Paper

Prognostic relevance of glucosylceramide synthase (GCS) expression in breast cancer

Authors: Eugen Ruckhäberle, Thomas Karn, Lars Hanker, Regine Gätje, Dirk Metzler, Uwe Holtrich, Manfred Kaufmann, Achim Rody

Published in: Journal of Cancer Research and Clinical Oncology | Issue 1/2009

Abstract

Purpose

Multidrug resistance (MDR) has been linked to sphingolipid metabolism and preclinical data ascribe glucosylceramide synthase (GCS) a major role for MDR especially in breast cancer cells but no profound data are available on the expression of this potential therapeutic target in clinical breast cancer specimens.

Methods

We analyzed microarray data of GCS expression in a large cohort of 1,681 breast tumors.

Results

Expression of GCS was associated with a positive estrogen receptor (ER) status, lower histological grading, low Ki67 levels and ErbB2 negativity (P < 0.001 for all). In univariate analysis there was a benefit for disease free survival for patients with tumors displaying low levels of GCS expression but this significance was lost in multivariate Cox regression.

Conclusions

Our results suggest ER positive tumors may be the most promising candidates for a potential therapeutic application of GCS inhibitors.

Ahr A, Karn T, Solbach C, Seiter T, Strebhardt K, Holtrich U et al (2002) Identification of high risk breast-cancer patients by gene expression profiling. Lancet 359(9301):131–132. doi:10.1016/S0140-6736(02)07337-3 PubMedCrossRef

Alexe G, Dalgin GS, Scanfeld D, Tamayo P, Mesirov JP, DeLisi C et al (2007) High expression of lymphocyte-associated genes in node-negative HER2+ breast cancers correlates with lower recurrence rates. Cancer Res 67(22):10669–10676. doi:10.1158/0008-5472.CAN-07-0539 PubMedCrossRef

Bembi B, Marchetti F, Guerci VI, Ciana G, Addobbati R, Grasso D et al (2006) Substrate reduction therapy in the infantile form of Tay-Sachs disease. Neurology 66(2):278–280. doi:10.1212/01.wnl.0000194225.78917.de PubMedCrossRef

Bonnefoi H, Potti A, Delorenzi M, Mauriac L, Campone M, Tubiana-Hulin M et al (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(12):1071–1078. doi:10.1016/S1470-2045(07)70345-5 PubMedCrossRef

Butters TD (2007) Pharmacotherapeutic strategies using small molecules for the treatment of glycolipid lysosomal storage disorders. Expert Opin Pharmacother 8(4):427–435. doi:10.1517/14656566.8.4.427 PubMedCrossRef

Chaudhary PM, Roninson IB (1993) Induction of multidrug resistance in human cells by transient exposure to different chemotherapeutic drugs. J Natl Cancer Inst 85:632–639. doi:10.1093/jnci/85.8.632 PubMedCrossRef

de Azambuja E, Cardoso F, de Castro G Jr, Colozza M, Mano MS, Durbecq V et al (2007) Ki-67 as prognostic marker in early breast cancer: a meta-analysis of published studies involving 12,155 patients. Br J Cancer 96(10):1504–1513. doi:10.1038/sj.bjc.6603756

Deffie AM, Batra JK, Goldenberg GJ (1989) Direct correlation between DNA topoisomerase II activity and ytotoxicity in Adriamycin-sensitive and -resistant P388 leukemia cell lines. Cancer Res 49:58–62PubMed

Deng W, Li R, Guerrera M, Liu Y, Ladisch S (2002) Transfection of glucosylceramide synthase antisense inhibits mouse melanoma formation. Glycobiology 12:145–152. doi:10.1093/glycob/12.3.145 PubMedCrossRef

Desmedt C, Piette F, Loi S, Wang Y, Lallemand F, Haibe-Kains B, et al. (2007) TRANSBIG Consortium. 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(11):3207–3214. doi:10.1158/1078-0432.CCR-06-2765

Di Sano F, Di Bartolomeo S, Fiorentini C, Matarrese P, Spinedi A, Piacentini M (2002) Antisense to glucosylceramide synthase in human neuroepithelioma affects cell growth but not apoptosis. Cell Death Differ 9:693–695. doi:10.1038/sj.cdd.4401040 PubMedCrossRef

Foekens JA, Atkins D, Zhang Y, Sweep FC, Harbeck N, Paradiso A et al (2006) Multicenter validation of a gene expression-based prognostic signature in lymph node-negative primary breast cancer. J Clin Oncol 24(11):1665–1671. doi:10.1200/JCO.2005.03.9115 PubMedCrossRef

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

Gong Y, Yan K, Lin F, Anderson K, Sotiriou C, Andre F et al (2007) Determination of oestrogen-receptor status and ERBB2 status of breast carcinoma: a gene-expression profiling study. Lancet Oncol 8(3):203–211. doi:10.1016/S1470-2045(07)70042-6 PubMedCrossRef

Gouaze V, Yu JY, Bleicher RJ, Han TY, Liu YY, Wang H et al (2004) Overexpression of glucosylceramide synthase and P-glycoprotein in cancer cells selected for resistance to natural product chemotherapy. Mol Cancer Ther 3:633–639PubMed

Gouaze-Andersson V, Cabot MC (2006) Glycosphingolipids and drug resistance. Biochim Biophys Acta 1758:2096–2103PubMedCrossRef

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 1771:1407–1417PubMed

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

Irizarry RA, Bolstad BM, Collin F, Cope LM, Hobbs B, Speed TP (2003) Summaries of Affymetrix GeneChip probe level data. Nucleic Acids Res 31(4):e15. doi:10.1093/nar/gng015

Jeckel D, Karrenbauer A, Burger KN, van Meer G, Wieland F (1992) Glucosylceramide is synthesized at the cytosolic surface of various Golgi subfractions. J Cell Biol 117:259–267. doi:10.1083/jcb.117.2.259 PubMedCrossRef

Jeyakumar M, Butters TD, Dwek RA, Platt FM (2002) Glycosphingolipid lysosomal storage diseases: therapy and pathogenesis. Neuropathol Appl Neurobiol 28(5):343–357. doi:10.1046/j.1365-2990.2002.00422.x PubMedCrossRef

Kohno K, Sato S, Takano H, Matsuo K, Kuwano M (1989) The direct activation of human multidrug resistance gene (MDR1) by anticancer agents. Biochem Biophys Res Commun 165:1415–1421. doi:10.1016/0006-291X(89)92761-7 PubMedCrossRef

Kok JW, Veldman RJ, Klappe K, Koning H, Filipeanu CM, Muller M (2000) Differential expression of sphingolipids in MRP1 overexpressing HT29 cells. Int J Cancer 87:172–178. doi:10.1002/1097-0215(20000715)87:2<172::AID-IJC3>3.0.CO;2-KPubMedCrossRef

Lachmann RH (2003) Miglustat Oxford glycoSciences/actelion. Curr Opin Investig Drugs 4:472–479PubMed

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. doi:10.1074/jbc.271.32.19530 PubMedCrossRef

Lavie Y, Cao H, Volner A, Lucci A, Han TY, Geffen V et al (1997) Agents that reverse multidrug resistance, tamoxifen, verapamil, and cyclosporin A, block glycosphingolipid metabolism by inhibiting ceramide glycosylation in human cancer cells. J Biol Chem 272:1682–1687. doi:10.1074/jbc.272.3.1682 PubMedCrossRef

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 PubMedCrossRef

Liu YY, Han TY, Giuliano AE, Cabot MC (1999a) Expression of glucosylceramide synthase, converting ceramide to glucosylceramide, confers adriamycin resistance in human breast cancer cells. J Biol Chem 274:1140–1146. doi:10.1074/jbc.274.2.1140 PubMedCrossRef

Liu YY, Han TY, Giuliano AE, Ichikawa S, Hirabayashi Y, Cabot MC (1999b) Glycosylation of ceramide potentiates cellular resistance to tumor necrosis factor-alpha-induced apoptosis. Exp Cell Res 252:464–470. doi:10.1006/excr.1999.4649 PubMedCrossRef

Liu YY, Han TY, Giuliano AE, Hansen N, Cabot MC (2000) Uncoupling ceramide glycosylation by transfection of glucosylceramide synthase antisense reverses adriamycin resistance. J Biol Chem 275:7138–7143. doi:10.1074/jbc.275.10.7138 PubMedCrossRef

Liu Y-Y, Han TY, Yu JY, Bitterman A, Le A, Giuliano AE et al (2004) Oligonucleotides blocking glucosylceramide synthase expression selectively reverse drug resistance in cancer cells. J Lipid Res 45:933–940. doi:10.1194/jlr.M300486-JLR200 PubMedCrossRef

Liu YY,, Yin D,, 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 [Epub ahead of print]

Loi S, Haibe-Kains B, Desmedt C, Lallemand F, Tutt AM, Gillet C et al (2007) Definition of clinically distinct molecular subtypes in estrogen receptor-positive breast carcinomas through genomic grade. J Clin Oncol 25(10):1239–1246. doi:10.1200/JCO.2006.07.1522 PubMedCrossRef

Lucci A, Cho WI, Han TY, Giuliano AE, Morton DL, Cabot MC (1998) Glucosylceramide: a marker for multiple-drug resistant cancers. Anticancer Res 18:475–480PubMed

Makin G, Dive C (2001) Apoptosis and cancer chemotherapy. Trends Cell Biol 11:S22–S26PubMed

Miller LD, Smeds J, George J, Vega VB, Vergara L, Ploner A et al (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. doi:10.1073/pnas.0506230102 PubMedCrossRef

Minn AJ, Gupta GP, Siegel PM, Bos PD, Shu W, Giri DD et al (2005) Genes that mediate breast cancer metastasis to lung. Nature 436(7050):518–524. doi:10.1038/nature03799 PubMedCrossRef

Minn AJ, Gupta GP, Padua D, Bos P, Nguyen DX, Nuyten D et al (2007) Lung metastasis genes couple breast tumor size and metastatic spread. Proc Natl Acad Sci USA 104(16):6740–6745. doi:10.1073/pnas.0701138104 PubMedCrossRef

Morjani H, Aouali N, Belhoussine R, Veldman RJ, Levade T, Manfait M (2001) Elevation of glucosylceramide in multidrug-resistant cancer cells and accumulation in cytoplasmic droplets. Int J Cancer 94:157–165. doi:10.1002/ijc.1449 PubMedCrossRef

Morrow CS, Cowan KH (1990) Glutathione S-transferases and drug resistance. Cancer Cells 2:15–22PubMed

Mueller H, Eppenberger U (1996) The dual role of mutant p53 protein in chemosensitivity of human cancers. Anticancer Res 16:3845–3848PubMed

Nicholson KM, Quinn DM, Kellett GL, Warr JR (1999) Preferential killing of multidrug-resistant KB cells by inhibitors of glucosylceramide synthase. Br J Cancer 81:423–430. doi:10.1038/sj.bjc.6690711 PubMedCrossRef

Norris-Cervetto E, Callaghan R, Platt FM, Dwek RA, Butters TD (2004) Inhibition of glucosylceramide synthase does not reverse drug resistance in cancer cells. J Biol Chem 279:40412–40418. doi:10.1074/jbc.M404466200 PubMedCrossRef

Ogretmen B, Hannun YA (2004) Biologically active sphingolipids in cancer pathogenesis and treatment. Nat Rev Cancer 4:604–616. doi:10.1038/nrc1411 PubMedCrossRef

Ogretmen B, Schady D, Usta J, Wood R, Kraveka JM, Luberto C et al (2001) Role of ceramide in mediating the inhibition of telomerase activity in A549 human lung adenocarcinoma cells. J Biol Chem 276:24901–24910. doi:10.1074/jbc.M100314200 PubMedCrossRef

Patterson MC, Vecchio D, Prady H, Abel L, Wraith JE (2007) Miglustat for treatment of Niemann-Pick C disease: a randomised controlled study. Lancet Neurol 6(9):765–772. doi:10.1016/S1474-4422(07)70194-1 PubMedCrossRef

Pawitan Y, Bjohle J, Amler L, Borg AL, Egyhazi S, Hall P et al (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. doi:10.1186/bcr1325 PubMedCrossRef

Radin NS, Shayman JA, Inokuchi J-I (1993) Metabolic effects of inhibiting glucosylceramide synthesis with PDMP and other substances. Adv Lipid Res 26:183–211PubMed

Reed JC (1995) Regulation of apoptosis by bcl-2 family proteins and its role in cancer and chemoresistance. Curr Opin Oncol 7:541–546. doi:10.1097/00001622-199511000-00012 PubMedCrossRef

Reynolds CP, Maurer BJ, Kolesnick RN (2004) Ceramide synthesis and metabolism as a target for cancer therapy. Cancer Lett 206:169–180. doi:10.1016/j.canlet.2003.08.034 PubMedCrossRef

Rody A, Holtrich U, Muller V, Gaetje R, Diallo R, Gehrmann M et al (2006) c-kit: identification of co-regulated genes by gene expression profiling and clinical relevance of two breast cancer subtypes with stem cell like features. ASCO annual meeting proceedings part I. J Clin Oncol 24:622

Rody A, Holtrich U, Gaetje R, Gehrmann M, Engels K, von Minckwitz G et al (2007) Poor outcome in estrogen receptor-positive breast cancers predicted by loss of plexin B1. Clin Cancer Res 13(4):1115–1122. doi:10.1158/1078-0432.CCR-06-2433 PubMedCrossRef

Ruckhäberle E, Rody A, Engels K, Gaetje R, von Minckwitz G, Schiffmann S, Grösch 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 [Epub ahead of print]

Shabbits JA, Mayer LD (2002) P-glycoprotein modulates ceramide-mediated sensitivity of human breast cancer cells to tubulin-binding anticancer drugs. Mol Cancer Ther 1:205–213PubMed

Shabbits JA, Krishna R, Mayer LD (2001) Molecular and pharmacological strategies to overcome multidrug resistance. Expert Rev Anticancer Ther 1:585–594. doi:10.1586/14737140.1.4.585 PubMedCrossRef

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

Sotiriou C, Wirapati P, Loi S, Harris A, Fox S, Smeds J et al (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

Spyratos F, Ferrero-Poüs M, Trassard M, Hacène K, Phillips E, Tubiana-Hulin M et al (2002) Correlation between MIB-1 and other proliferation markers: clinical implications of the MIB-1 cutoff value. Cancer 94(8):2151–2159. doi:10.1002/cncr.10458 PubMedCrossRef

Tifft CJ, Proia RJ (2000) Stemming the tide: glycosphingolipids synthesis inhibitors as therapy for storage diseases. Glycobiology 10:1249–1258. doi:10.1093/glycob/10.12.1249 PubMedCrossRef

Wang Y, Klijn JG, Zhang Y, Sieuwerts AM, Look MP, Yang F et al (2005) Gene-expression profiles to predict distant metastasis of lymph-node-negative primary breast cancer. Lancet 365(9460):671–679PubMed

Weiss M, Hettmer S, Smith P, Ladisch S (2003) Inhibition of melanoma tumor growth by a novel inhibitor of glucosylceramide synthase. Cancer Res 63(13):3654–3658PubMed

Title: Prognostic relevance of glucosylceramide synthase (GCS) expression in breast cancer
Authors: Eugen Ruckhäberle
Thomas Karn
Lars Hanker
Regine Gätje
Dirk Metzler
Uwe Holtrich
Manfred Kaufmann
Achim Rody
Publication date: 01-01-2009
Publisher: Springer-Verlag
Published in: Journal of Cancer Research and Clinical Oncology / Issue 1/2009
Print ISSN: 0171-5216
Electronic ISSN: 1432-1335
DOI: https://doi.org/10.1007/s00432-008-0436-9

Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin

Prof. Florian Limbourg

Prof. Anoop Chauhan

Developed by: Springer Medicine

Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits

Illustration of figure on mountain summit/© Orapun / Stock.adobe.com, STEP AAG HeroTeaserCollection image/© Tarek / Generated with AI / Stock.adobe.com, ACC 2024 Pediatric and Congenital Heart Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 Pulmonary Vascular Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 Valvular Heart Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 HF and Cardiomyopathies: Year in Review/© 2024 American College of Cardiology, Woman out walking/© Seventyfour / stock.adobe.com (symbolic image with model), Woman checking smartwatch /© saltdium / stock.adobe.com (symbolic image with model), Cardiac catheterization/© Damian / stock.adobe.com

At a glance: The STEP trials

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2009

Pathogenesis of malignant pleural mesothelioma and the role of environmental and genetic factors

Preoperative hemoglobin and platelet count and poor prognostic factors in patients with endometrial carcinoma

Treatment options for recurrent giant cell tumors of bone

Current strategies in systemic treatment of gastric cancer and cancer of the gastroesophageal junction

Pre-treatment global quality of health predicts progression free survival in metastatic kidney cancer patients treated with sorafenib or sunitinib

Differential IL-4/Stat6 activities correlate with differential expression of regulatory genes SOCS-1, SHP-1, and PP2A in colon cancer cells

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

Highlights from the ACC 2024 Congress

ACC 2024 Congress Coverage