Oncotarget

Research Papers:

Interaction of glycosphingolipids GD3 and GD2 with growth factor receptors maintains breast cancer stem cell phenotype

Yuh-Jin Liang, Chen-Yu Wang, I-An Wang, Yi-Wen Chen, Li-Tzu Li, Chuang-Yu Lin, Ming-Yi Ho, Tsung-Lung Chou, Ya-Hui Wang, Shih-Pin Chiou, Yu-Ju Lin and John Yu _

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Oncotarget. 2017; 8:47454-47473. https://doi.org/10.18632/oncotarget.17665

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Abstract

Yuh-Jin Liang1, Chen-Yu Wang2, I-An Wang1, Yi-Wen Chen1, Li-Tzu Li1, Chuang-Yu Lin1, Ming-Yi Ho1, Tsung-Lung Chou1, Ya-Hui Wang1, Shih-Pin Chiou1, Yu-Ju Lin1 and John Yu1,3

1Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan

2Department of Physiology and Pharmacology, College of Medicine, Chang Gung University, Taoyuan, Taiwan

3Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan

Correspondence to:

John Yu, email: johnyu@gate.sinica.edu.tw

Yuh-Jin Liang, email: yuh.jin.liang@gmail.com

Keywords: glycosphingolipid, ganglioside, breast cancer stem cell, GD3 synthase, glycosyltransferase

Received: January 06, 2017     Accepted: April 19, 2017     Published: May 07, 2017

ABSTRACT

Many studies have suggested that disialogangliosides, GD2 and GD3, are involved in the development of various tumor types. However, the functional relationships between ganglioside expression and cancer development or aggressiveness are not fully described. GD3 is upregulated in approximately half of all invasive ductal breast carcinoma cases, and enhanced expression of GD3 synthase (GD3S, alpha-N-acetylneuraminide alpha-2,8-sialyltransferase) in estrogen receptor-negative breast tumors, was shown to correlate with reduced overall patient survival. We previously found that GD2 and GD3, together with their common upstream glycosyltransferases, GD3S and GD2/GM2 synthase, maintain a stem cell phenotype in breast cancer stem cells (CSCs). In the current study, we demonstrate that GD3S alone can sustain CSC properties and also promote malignant cancer properties. Using MALDI-MS and flow cytometry, we found that breast cancer cell lines, of various subtypes with or without ectopic GD3S-expression, exhibited distinct GD2/GD3 expression profiles. Furthermore, we found that GD3 was associated with EGFR and activated EGFR signaling in both breast CSCs and breast cancer cell lines. In addition, GD3S knockdown enhanced cytotoxicity of the EGFR-inhibitor gefitinib in resistant MDA-MB468 cells, both in vitro and in vivo. Based on this evidence, we propose that GD3S contributes to gefitinib-resistance in EGFR-positive breast cancer cells and may be an effective therapeutic target in drug-resistant breast cancers.


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