title: The sialyl-glycolipid stage-specific embryonic antigen 4 marks a subpopulation of chemotherapy-resistant breast cancer cells with mesenchymal features.
abstract: BACKGROUND
  Chemotherapy resistance resulting in incomplete pathologic response is associated with high risk of metastasis and early relapse in breast cancer. The aim of this study was to identify and evaluate biomarkers of treatment-resistant tumor cells.
  
  
  METHODS
  We performed a cell surface marker screen in triple-negative breast cancer patient-derived xenograft models treated with standard care genotoxic chemotherapy. Global expression profiling was used to further characterize the identified treatment-resistant subpopulations.
  
  
  RESULTS
  High expression of sialyl-glycolipid stage-specific embryonic antigen 4 (SSEA4) was found in residual tumor cells surviving chemotherapy and in samples from metastatic patients who relapsed after neoadjuvant chemotherapy. Gene and microRNA (miRNA) expression profiling linked SSEA4 positivity with a mesenchymal phenotype and a deregulation of drug resistance pathways. Functional assays demonstrated a direct link between epithelial-mesenchymal transition (EMT) and SSEA4 expression. Interestingly, SSEA4 expression, EMT, and drug resistance seemed to be regulated posttranscriptionally. Finally, high expression of CMP-N-acetylneuraminate-β-galactosamide-α-2,3-sialyltransferase 2 (ST3GAL2), the rate-limiting enzyme of SSEA4 synthesis, was found to be associated with poor clinical outcome in breast and ovarian cancer patients treated with chemotherapy.
  
  
  CONCLUSIONS
  In this study, we identified SSEA4 as highly expressed in a subpopulation of tumor cells resistant to multiple commonly used chemotherapy drugs, as well as ST3GAL2, the rate-limiting enzyme of SSEA4 synthesis, as a predictive marker of poor outcome for breast and ovarian cancer patients undergoing chemotherapy. Both biomarkers and additionally identified regulatory miRNAs may be used to further understand chemoresistance, to stratify patient groups in order to avoid ineffective and painful therapies, and to develop alternative treatment regimens for breast cancer patients.
authors.affiliation: Miltenyi Biotec GmbH, Friedrich-Ebert-Strasse 68, 51429, Bergisch Gladbach, Germany. aloia.andrea@libero.it.
authors.forename: Andrea
authors.initials: A
authors.lastname: Aloia
authors.affiliation: XenTech SAS, 4 rue Pierre Fontaine, 91000, Evry, France. epetrova@pasteur.fr.|Present address: Department of Virology, Pasteur Institute, 25-28 Rue du Docteur Roux, 75015, Paris, France. epetrova@pasteur.fr.
authors.forename: Evgeniya
authors.initials: E
authors.lastname: Petrova
authors.affiliation: Miltenyi Biotec GmbH, Friedrich-Ebert-Strasse 68, 51429, Bergisch Gladbach, Germany. stefant@miltenyibiotec.de.
authors.forename: Stefan
authors.initials: S
authors.lastname: Tomiuk
authors.affiliation: Miltenyi Biotec GmbH, Friedrich-Ebert-Strasse 68, 51429, Bergisch Gladbach, Germany. ute@miltenyibiotec.de.
authors.forename: Ute
authors.initials: U
authors.lastname: Bissels
authors.affiliation: XenTech SAS, 4 rue Pierre Fontaine, 91000, Evry, France. olivier.deas@xentech.eu.
authors.forename: Olivier
authors.initials: O
authors.lastname: Déas
authors.affiliation: Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM) gGmbH, Im Neuenheimer Feld 280, 69120, Heidelberg, Germany. massimo.saini@hi-stem.de.|Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany. massimo.saini@hi-stem.de.
authors.forename: Massimo
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authors.lastname: Saini
authors.affiliation: Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM) gGmbH, Im Neuenheimer Feld 280, 69120, Heidelberg, Germany. f.zickgraf@dkfz-heidelberg.de.|Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany. f.zickgraf@dkfz-heidelberg.de.
authors.forename: Franziska Maria
authors.initials: FM
authors.lastname: Zickgraf
authors.affiliation: Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM) gGmbH, Im Neuenheimer Feld 280, 69120, Heidelberg, Germany. steve.wagner@icr.ac.uk.|Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany. steve.wagner@icr.ac.uk.
authors.forename: Steve
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authors.lastname: Wagner
authors.affiliation: Frauenklinik, University Medical Centre Mannheim, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany. saskia.spaich@umm.de.
authors.forename: Saskia
authors.initials: S
authors.lastname: Spaich
authors.affiliation: Frauenklinik, University Medical Centre Mannheim, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany. marc.suetterlin@umm.de.
authors.forename: Marc
authors.initials: M
authors.lastname: Sütterlin
authors.affiliation: National Center for Tumor Diseases, University Hospital Heidelberg, Im Neuenheimer Feld 460, 69120, Heidelberg, Germany. andreas.schneeweiss@nct-heidelberg.de.
authors.forename: Andreas
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authors.lastname: Schneeweiss
authors.affiliation: Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM) gGmbH, Im Neuenheimer Feld 280, 69120, Heidelberg, Germany. m.reitberger@dkfz-heidelberg.de.|Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany. m.reitberger@dkfz-heidelberg.de.
authors.forename: Manuel
authors.initials: M
authors.lastname: Reitberger
authors.affiliation: Miltenyi Biotec GmbH, Friedrich-Ebert-Strasse 68, 51429, Bergisch Gladbach, Germany. silvia@miltenyibiotec.de.
authors.forename: Silvia
authors.initials: S
authors.lastname: Rüberg
authors.affiliation: Miltenyi Biotec GmbH, Friedrich-Ebert-Strasse 68, 51429, Bergisch Gladbach, Germany. bernhard@miltenyibiotec.de.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Gerstmayer
authors.affiliation: Miltenyi Biotec GmbH, Friedrich-Ebert-Strasse 68, 51429, Bergisch Gladbach, Germany. davida@miltenyibiotec.de.
authors.forename: David
authors.initials: D
authors.lastname: Agorku
authors.affiliation: Miltenyi Biotec GmbH, Friedrich-Ebert-Strasse 68, 51429, Bergisch Gladbach, Germany. sebastiank@miltenyibiotec.de.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Knöbel
authors.affiliation: Sidra Medical and Research Center, PO Box 26999, Doha, Qatar. aterranegra@sidra.org.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Terranegra
authors.affiliation: Department of Health Sciences, University of Milan, Via Festa del Perdono 7, 20122, Milan, Italy. monica.falleni@unimi.it.
authors.forename: Monica
authors.initials: M
authors.lastname: Falleni
authors.affiliation: Department of Health Sciences, University of Milan, Via Festa del Perdono 7, 20122, Milan, Italy. laura.soldati@unimi.it.
authors.forename: Laura
authors.initials: L
authors.lastname: Soldati
authors.affiliation: Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM) gGmbH, Im Neuenheimer Feld 280, 69120, Heidelberg, Germany. martin.sprick@hi-stem.de.|Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany. martin.sprick@hi-stem.de.
authors.forename: Martin Ronald
authors.initials: MR
authors.lastname: Sprick
authors.affiliation: Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM) gGmbH, Im Neuenheimer Feld 280, 69120, Heidelberg, Germany. a.trumpp@dkfz-heidelberg.de.|Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany. a.trumpp@dkfz-heidelberg.de.|German Cancer Consortium, Im Neuenheimer Feld 280, 69120, Heidelberg, Germany. a.trumpp@dkfz-heidelberg.de.
authors.forename: Andreas
authors.initials: A
authors.lastname: Trumpp
authors.affiliation: XenTech SAS, 4 rue Pierre Fontaine, 91000, Evry, France. jgjudde@xentech.eu.
authors.forename: Jean-Gabriel
authors.initials: JG
authors.lastname: Judde
authors.affiliation: Miltenyi Biotec GmbH, Friedrich-Ebert-Strasse 68, 51429, Bergisch Gladbach, Germany. andreasbo@miltenyibiotec.de.
authors.forename: Andreas
authors.initials: A
authors.lastname: Bosio
authors.affiliation: XenTech SAS, 4 rue Pierre Fontaine, 91000, Evry, France. Stefano.Cairo@xentech.eu.|University of Ferrara, LTTA Centre,Department of Morphology, Surgery and Experimental Medicine, Via Fossato di Mortara 70, 44121, Ferrara, Italy. Stefano.Cairo@xentech.eu.
authors.forename: Stefano
authors.initials: S
authors.lastname: Cairo
authors.affiliation: Miltenyi Biotec GmbH, Friedrich-Ebert-Strasse 68, 51429, Bergisch Gladbach, Germany. olaf@miltenyibiotec.de.
authors.forename: Olaf
authors.initials: O
authors.lastname: Hardt
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D006801:Humans; D051379:Mice; D009368:Neoplasm Transplantation; D055746:Stage-Specific Embryonic Antigens / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; D055746:Stage-Specific Embryonic Antigens; C066584:stage-specific embryonic antigen-4