The sialyl-glycolipid stage-specific embryonic antigen 4 marks a subpopulation of chemotherapy-resistant breast cancer cells with mesenchymal featuresReport as inadecuate

The sialyl-glycolipid stage-specific embryonic antigen 4 marks a subpopulation of chemotherapy-resistant breast cancer cells with mesenchymal features - Download this document for free, or read online. Document in PDF available to download.

Breast Cancer Research

, 17:146

First Online: 25 November 2015Received: 01 April 2015Accepted: 16 September 2015DOI: 10.1186-s13058-015-0652-6

Cite this article as: Aloia, A., Petrova, E., Tomiuk, S. et al. Breast Cancer Res 2015 17: 146. doi:10.1186-s13058-015-0652-6


IntroductionChemotherapy 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.

MethodsWe 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.

ResultsHigh 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.

ConclusionsIn 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.




CTCcirculating tumor cell


EMTepithelial–mesenchymal transition

EpCAMepithelial cell adhesion molecule

ERestrogen receptor

FIGOInternational Federation of Gynecologists and Obstetricians

FITCfluorescein isothiocyanate

FSCforward scatter

FSC-Aforward scatter area

FSC-Hforward scatter height

GEOGene Expression Omnibus


HBCxhuman breast cancer xenograft

IC50half-maximal inhibitory concentration

MFImedian fluorescence intensity

miRNAmicroRNA, mIR

mRAmessenger RNA

PDXpatient-derived xenograft

PEpleural effusion

PIpropidium iodide

PRprogesterone receptor

RCCrenal cell carcinoma

siRNAsmall interfering RNA

SSCside scatter

SSEA4sialyl-glycolipid stage-specific embryonic antigen 4

ST3GAL2CMP-N-acetylneuraminate-β-galactosamide-α-2,3-sialyltransferase 2

TGFtransforming growth factor


TNBCtriple-negative breast cancer

Andrea Aloia and Evgeniya Petrova are co–first authors.

Stefano Cairo and Olaf Hardt are co–senior authors.

Electronic supplementary materialThe online version of this article doi:10.1186-s13058-015-0652-6 contains supplementary material, which is available to authorized users.

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Author: Andrea Aloia - Evgeniya Petrova - Stefan Tomiuk - Ute Bissels - Olivier Déas - Massimo Saini - Franziska Maria Zickgraf -


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