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Prognostic relevance of glycosylation-associated genes in breast cancer

  • Preclinical study
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Abstract

Glycosylation of cellular proteins has important impact on their stability and functional properties, and glycan structures strongly influence cell adhesion. Many enzymes are involved in glycoconjugate synthesis and degradation, but there is only limited information about their role in breast cancer progression. Therefore, we retrieved RNA expression data of 202 glycosylation genes generated by microarray analysis (Affymetrix HG-U133A) in a cohort of 194 mammary carcinomas with long-term follow-up information. After univariate and multivariate Cox regression analysis, genes with independent prognostic value were identified. These were further analysed by Kaplan–Meier analysis and log-rank tests, and their prognostic value was validated in a second cohort of 200 tumour samples from patients without systemic therapy. In our first cohort, we identified 24 genes with independent prognostic value, coding for sixteen anabolic and eight catabolic enzymes. Functionally, these genes are involved in all important glycosylation pathways, namely O-glycosylation, N-glycosylation, O-fucosylation, synthesis of glycosaminoglycans and glycolipids. Eighteen genes also showed prognostic significance in chemotherapy-treated patients. In the second cohort, six of the 24 relevant genes were of prognostic significance (FUT1, FUCA1, POFUT1, MAN1A1, RPN1 and DPM1), whereas a trend was observed for three additional probesets (GCNT4, ST3GAL6 and UGCG). In a stratified analysis of molecular subtypes combining both cohorts, great differences appeared suggesting a predominant role of N-glycosylation in luminal cancers and O-glycosylation in triple-negative ones. Correlations of gene expression with metastases of various localizations point to a role of glycan structures in organ-specific metastatic spread. Our results indicate that various glycosylation reactions influence progression and metastasis of breast cancer and might thus represent potential therapeutic targets.

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References

  1. Afratis N, Gialeli C, Nikitovic D, Tsegenidis T, Karousou E, Theocharis AD, Pavao MS, Tzanakakis GN, Karamanos NK (2012) Glycosaminoglycans: key players in cancer cell biology and treatment. FEBS J 279:1177–1197. doi:10.1111/j.1742-4658.2012.08529.x

    Article  CAS  PubMed  Google Scholar 

  2. Arcaro KF, Wang J, Otis CN, Zuckerman BM (2004) Beta-galactosidase and alpha-mannosidase inhibit formation of multicellular nodules in breast cancer cell cultures. Anticancer Res 24:139–144

    CAS  PubMed  Google Scholar 

  3. Auvinen P, Tammi R, Parkkinen J, Tammi M, Agren U, Johansson R, Hirvikoski P, Eskelinen M, Kosma VM (2000) Hyaluronan in peritumoral stroma and malignant cells associates with breast cancer spreading and predicts survival. Am J Pathol 156:529–536. doi:10.1016/S0002-9440(10)64757-8

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  4. Brockhausen I (2006) Mucin-type O-glycans in human colon and breast cancer: glycodynamics and functions. EMBO Rep 7:599–604

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. Brockhausen I (1999) Pathways of O-glycan biosynthesis in cancer cells. Biochim Biophys Acta 1473:67–95

    Article  CAS  PubMed  Google Scholar 

  6. Carvalho AS, Harduin-Lepers A, Magalhaes A, Machado E, Mendes N, Costa LT, Matthiesen R, Almeida R, Costa J, Reis CA (2010) Differential expression of alpha-2,3-sialyltransferases and alpha-1,3/4-fucosyltransferases regulates the levels of sialyl Lewis a and sialyl Lewis x in gastrointestinal carcinoma cells. Int J Biochem Cell Biol 42:80–89. doi:10.1016/j.biocel.2009.09.010

    Article  CAS  PubMed  Google Scholar 

  7. Cazet A, Julien S, Bobowski M, Burchell J, Delannoy P (2010) Tumour-associated carbohydrate antigens in breast cancer. Breast Cancer Res BCR 12:204. doi:10.1186/bcr2577

    Article  Google Scholar 

  8. Contessa JN, Bhojani MS, Freeze HH, Ross BD, Rehemtulla A, Lawrence TS (2010) Molecular imaging of N-linked glycosylation suggests glycan biosynthesis is a novel target for cancer therapy. Clin Cancer Res 16:3205–3214. doi:10.1158/1078-0432.CCR-09-3331

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Cooney CA, Jousheghany F, Yao-Borengasser A, Phanavanh B, Gomes T, Kieber-Emmons AM, Siegel ER, Suva LJ, Ferrone S, Kieber-Emmons T, Monzavi-Karbassi B (2011) Chondroitin sulfates play a major role in breast cancer metastasis: a role for CSPG4 and CHST11 gene expression in forming surface P-selectin ligands in aggressive breast cancer cells. Breast Cancer Res BCR 13:R58. doi:10.1186/bcr2895

    Article  CAS  Google Scholar 

  10. Gotte M, Yip GW (2006) Heparanase, hyaluronan, and CD44 in cancers: a breast carcinoma perspective. Cancer Res 66:10233–10237. doi:10.1158/0008-5472.CAN-06-1464

    Article  PubMed  Google Scholar 

  11. Goupille C, Marionneau S, Bureau V, Hallouin F, Meichenin M, Rocher J, Le Pendu J (2000) Alpha1,2fucosyltransferase increases resistance to apoptosis of rat colon carcinoma cells. Glycobiology 10:375–382

    Article  CAS  PubMed  Google Scholar 

  12. Guo Q, Guo B, Wang Y, Wu J, Jiang W, Zhao S, Qiao S, Wu Y (2012) Functional analysis of alpha1,3/4-fucosyltransferase VI in human hepatocellular carcinoma cells. Biochem Biophys Res Commun 417:311–317. doi:10.1016/j.bbrc.2011.11.106

    Article  CAS  PubMed  Google Scholar 

  13. Hatakeyama S, Kyan A, Yamamoto H, Okamoto A, Sugiyama N, Suzuki Y, Yoneyama T, Hashimoto Y, Koie T, Yamada S, Saito H, Arai Y, Fukuda M, Ohyama C (2010) Core 2 N-acetylglucosaminyltransferase-1 expression induces aggressive potential of testicular germ cell tumor. Int J Cancer 127:1052–1059. doi:10.1002/ijc.25117

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Hu YY, Zheng MH, Zhang R, Liang YM, Han H (2012) Notch signaling pathway and cancer metastasis. Adv Exp Med Biol 727:186–198. doi:10.1007/978-1-4614-0899-4_14

    Article  CAS  PubMed  Google Scholar 

  15. Ihnen M, Muller V, Wirtz RM, Schroder C, Krenkel S, Witzel I, Lisboa BW, Janicke F, Milde-Langosch K (2008) Predictive impact of activated leukocyte cell adhesion molecule (ALCAM/CD166) in breast cancer. Breast Cancer Res Treat 112(3):419–427

    Article  CAS  PubMed  Google Scholar 

  16. Julien S, Ivetic A, Grigoriadis A, QiZe D, Burford B, Sproviero D, Picco G, Gillett C, Papp SL, Schaffer L, Tutt A, Taylor-Papadimitriou J, Pinder SE, Burchell JM (2011) Selectin ligand sialyl-Lewis x antigen drives metastasis of hormone-dependent breast cancers. Cancer Res 71:7683–7693. doi:10.1158/0008-5472.CAN-11-1139

    Article  CAS  PubMed  Google Scholar 

  17. Kanoh A, Ota M, Narimatsu H, Irimura T (2003) Expression levels of FUT6 gene transfected into human colon carcinoma cells switch two sialyl-Lewis X-related carbohydrate antigens with distinct properties in cell adhesion. Biochem Biophys Res Commun 303:896–901

    Article  CAS  PubMed  Google Scholar 

  18. Karn T, Metzler D, Ruckhaberle E, Hanker L, Gatje R, Solbach C, Ahr A, Schmidt M, Holtrich U, Kaufmann M, Rody A (2010) Data-driven derivation of cutoffs from a pool of 3,030 Affymetrix arrays to stratify distinct clinical types of breast cancer. Breast Cancer Res Treat 120:567–579. doi:10.1007/s10549-009-0416-z

    Article  PubMed  Google Scholar 

  19. Kikuchi J, Ozaki H, Nonomura C, Shinohara H, Iguchi S, Nojiri H, Hamada H, Kiuchi A, Nakamura M (2005) Transfection of antisense core 2 beta1,6-N-acetylglucosaminyltransferase-1 cDNA suppresses selectin ligand expression and tissue infiltration of B-cell precursor leukemia cells. Leukemia 19:1934–1940. doi:10.1038/sj.leu.2403951

    Article  CAS  PubMed  Google Scholar 

  20. Lau KS, Dennis JW (2008) N-Glycans in cancer progression. Glycobiology 18:750–760. doi:10.1093/glycob/cwn071

    Article  CAS  PubMed  Google Scholar 

  21. Listinsky JJ, Siegal GP, Listinsky CM (2011) The emerging importance of alpha-l-fucose in human breast cancer: a review. Am J Transl Res 3:292–322

    CAS  PubMed Central  PubMed  Google Scholar 

  22. Martinez P, Vergoten G, Colomb F, Bobowski M, Steenackers A, Carpentier M, Allain F, Delannoy P, Julien S (2013) Over-sulfated glycosaminoglycans are alternative selectin ligands: insights into molecular interactions and possible role in breast cancer metastasis. Clin Exp Metastasis. doi:10.1007/s10585-013-9592-7

    Google Scholar 

  23. McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM (2006) REporting recommendations for tumor MARKer prognostic studies (REMARK). Breast Cancer Res Treat 100:229–235

    Article  PubMed  Google Scholar 

  24. Milde-Langosch K, Karn T, Muller V, Witzel I, Rody A, Schmidt M, Wirtz RM (2013) Validity of the proliferation markers Ki67, TOP2A, and RacGAP1 in molecular subgroups of breast cancer. Breast Cancer Res Treat 137:57–67. doi:10.1007/s10549-012-2296-x

    Article  CAS  PubMed  Google Scholar 

  25. Miles FL, Pruitt FL, van Golen KL, Cooper CR (2008) Stepping out of the flow: capillary extravasation in cancer metastasis. Clin Exp Metastasis 25:305–324

    Article  CAS  PubMed  Google Scholar 

  26. Moremen KW, Tiemeyer M, Nairn AV (2012) Vertebrate protein glycosylation: diversity, synthesis and function. Nat Rev Mol Cell Biol 13:448–462. doi:10.1038/nrm3383

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Nairn AV, Aoki K, dela Rosa M, Porterfield M, Lim JM, Kulik M, Pierce JM, Wells L, Dalton S, Tiemeyer M, Moremen KW (2012) Regulation of glycan structures in murine embryonic stem cells: combined transcript profiling of glycan-related genes and glycan structural analysis. J Biol Chem 287:37835–37856. doi:10.1074/jbc.M112.405233

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Perez-Garay M, Arteta B, Llop E, Cobler L, Pages L, Ortiz R, Ferri MJ, de Bolos C, Figueras J, de Llorens R, Vidal-Vanaclocha F, Peracaula R (2013) Alpha2,3-Sialyltransferase ST3Gal IV promotes migration and metastasis in pancreatic adenocarcinoma cells and tends to be highly expressed in pancreatic adenocarcinoma tissues. Int J Biochem Cell Biol 45:1748–1757. doi:10.1016/j.biocel.2013.05.015

    Article  CAS  PubMed  Google Scholar 

  29. Potapenko IO, Haakensen VD, Luders T, Helland A, Bukholm I, Sorlie T, Kristensen VN, Lingjaerde OC, Borresen-Dale AL (2010) Glycan gene expression signatures distinguish normal and malignant breast tissue; possible role in diagnosis and progression. EJC Suppl 8:102

    Article  Google Scholar 

  30. Renkonen J, Rabina J, Mattila P, Grenman R, Renkonen R (2001) Core 2 beta1,6-N-acetylglucosaminyltransferases and alpha1,3-fucosyltransferases regulate the synthesis of O-glycans on selectin ligands on oral cavity carcinoma cells. APMIS Acta Pathol Microbiol Immunol Scand 109:500–506

    Article  CAS  Google Scholar 

  31. Roberts JD, Klein JL, Palmantier R, Dhume ST, George MD, Olden K (1998) The role of protein glycosylation inhibitors in the prevention of metastasis and therapy of cancer. Cancer Detect Prev 22:455–462

    Article  CAS  PubMed  Google Scholar 

  32. Schmidt M, Bohm D, von Torne C, Steiner E, Puhl A, Pilch H, Lehr HA, Hengstler JG, Kolbl H, Gehrmann M (2008) The humoral immune system has a key prognostic impact in node-negative breast cancer. Cancer Res 68:5405–5413

    Article  CAS  PubMed  Google Scholar 

  33. Shirure VS, Henson KA, Schnaar RL, Nimrichter L, Burdick MM (2011) Gangliosides expressed on breast cancer cells are E-selectin ligands. Biochem Biophys Res Commun 406:423–429. doi:10.1016/j.bbrc.2011.02.061

    Article  CAS  PubMed  Google Scholar 

  34. Stern R (2005) Hyaluronan metabolism: a major paradox in cancer biology. Pathol Biol 53:372–382. doi:10.1016/j.patbio.2004.12.021

    Article  CAS  PubMed  Google Scholar 

  35. Suzuki Y, Sutoh M, Hatakeyama S, Mori K, Yamamoto H, Koie T, Saitoh H, Yamaya K, Funyu T, Habuchi T, Arai Y, Fukuda M, Ohyama C, Tsuboi S (2012) MUC1 carrying core 2 O-glycans functions as a molecular shield against NK cell attack, promoting bladder tumor metastasis. Int J Oncol 40:1831–1838. doi:10.3892/ijo.2012.1411

    CAS  PubMed Central  PubMed  Google Scholar 

  36. Taylor-Papadimitriou J, Epenetos AA (1994) Exploiting altered glycosylation patterns in cancer: progress and challenges in diagnosis and therapy. Trends Biotechnol 12:227–233. doi:10.1016/0167-7799(94)90121-X

    Article  CAS  PubMed  Google Scholar 

  37. Udabage L, Brownlee GR, Waltham M, Blick T, Walker EC, Heldin P, Nilsson SK, Thompson EW, Brown TJ (2005) Antisense-mediated suppression of hyaluronan synthase 2 inhibits the tumorigenesis and progression of breast cancer. Cancer Res 65:6139–6150. doi:10.1158/0008-5472.CAN-04-1622

    Article  CAS  PubMed  Google Scholar 

  38. Varki A, Lowe JB (2009) Biological roles of glycans. In: Varki A, Cummings RD, Esko JD, Freeze HH, Stanley P, Bertozzi CR, Hart GW, Etzler ME (eds) Essentials of glycobiology. Cold Spring Harbor, New York

    Google Scholar 

  39. Yuan K, Kucik D, Singh RK, Listinsky CM, Listinsky JJ, Siegal GP (2008) Alterations in human breast cancer adhesion-motility in response to changes in cell surface glycoproteins displaying alpha-l-fucose moieties. Int J Oncol 32:797–807

    CAS  PubMed Central  PubMed  Google Scholar 

  40. Yuan K, Listinsky CM, Singh RK, Listinsky JJ, Siegal GP (2008) Cell surface associated alpha-l-fucose moieties modulate human breast cancer neoplastic progression. Pathol Oncol Res POR 14:145–156. doi:10.1007/s12253-008-9036-x

    Article  CAS  Google Scholar 

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Acknowledgments

We are grateful to Katrin Beck, Sylke Krenkel, Maila Rossberg and Kathrin Eylmann for excellent technical assistance.

Conflict of interest

R.M. Wirtz is an employee of a diagnostic company. The other authors have no competing interests.

Author information

Authors and Affiliations

  1. Department of Gynecology, University Hospital Hamburg-Eppendorf, Hamburg, Germany

    Karin Milde-Langosch, Leticia Oliveira-Ferrer, Isabell Witzel, Dina Schütze & Volkmar Müller

  2. Department of Obstetrics and Gynecology, Goethe-University Frankfurt, Frankfurt am Main, Germany

    Thomas Karn

  3. Department of Obstetrics and Gynecology, Johannes Gutenberg-University Mainz, Mainz, Germany

    Marcus Schmidt

  4. Department of Medical Biometry and Epidemiology, University Hospital Hamburg-Eppendorf, Hamburg, Germany

    Christine zu Eulenburg

  5. STRATIFYER Molecular Pathology GmbH, Cologne, Germany

    Ralph M. Wirtz

  6. Department of Anatomy and Experimental Morphology, University Hospital Hamburg-Eppendorf, Hamburg, Germany

    Udo Schumacher

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  1. Karin Milde-Langosch
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  2. Thomas Karn
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  3. Marcus Schmidt
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Correspondence to Karin Milde-Langosch.

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Milde-Langosch, K., Karn, T., Schmidt, M. et al. Prognostic relevance of glycosylation-associated genes in breast cancer. Breast Cancer Res Treat 145, 295–305 (2014). https://doi.org/10.1007/s10549-014-2949-z

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