Exostosin 1 regulates cancer cell stemness in doxorubicin-resistant breast cancer cells

Manandhar, Sarala; Kim, Chang-Gu; Lee, Sunhee; Kang, Shin-Hyung; Basnet, Nikita; Lee, You Mie

doi:10.18632/oncotarget.19737

Cited by 26 publications

(19 citation statements)

References 53 publications

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“…Exostoxin 1 (EXT1) is an endoplasmic reticulum (ER)-residing type II transmembrane glycoprotein involved in the biosynthesis of cell surface heparin sulfate (HS). EXT1 promotes epithelial–mesenchymal transition (EMT) and migratory behavior in breast cancer cells [25]. Whipple et al reported that GPC1 plays an important role in tumor development and metastasis in pancreatic ductal adenocarcinoma [26].…”

Section: Discussionmentioning

confidence: 99%

Identification of a novel glycolysis-related gene signature for predicting metastasis and survival in patients with lung adenocarcinoma

2019

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Background: Lung cancer (LC) is one of the most lethal and most prevalent malignant tumors, and its incidence and mortality are increasing annually. Lung adenocarcinoma (LUAD) is the most common pathological type of lung cancer. Several biomarkers have been confirmed by data excavation to be related to metastasis, prognosis and survival. However, the moderate predictive effect of a single gene biomarker is not sufficient. Thus, we aimed to identify new gene signatures to better predict the possibility of LUAD. Methods:Using an mRNA-mining approach, we performed mRNA expression profiling in large LUAD cohorts (n = 522) from The Cancer Genome Atlas (TCGA) database. Gene Set Enrichment Analysis (GSEA) was performed, and connections between genes and glycolysis were found in the Cox proportional regression model. Results:We confirmed a set of nine genes (HMMR, B4GALT1, SLC16A3, ANGPTL4, EXT1, GPC1, RBCK1, SOD1, and AGRN) that were significantly associated with metastasis and overall survival (OS) in the test series. Based on this nine-gene signature, the patients in the test series could be divided into high-risk and low-risk groups. Additionally, multivariate Cox regression analysis revealed that the prognostic power of the nine-gene signature is independent of clinical factors. Conclusion:Our study reveals a connection between the nine-gene signature and glycolysis. This research also provides novel insights into the mechanisms underlying glycolysis and offers a novel biomarker of a poor prognosis and metastasis for LUAD patients.

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Section: Discussionmentioning

confidence: 99%

Identification of a novel glycolysis-related gene signature for predicting metastasis and survival in patients with lung adenocarcinoma

2019

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“…Furthermore, overexpression of EXT1 in a non-tumorigenic epithelial cell line transformed these cells to a more malignant phenotype, whereas siRNA mediated down-regulation of EXT1 in and ER-positive breast cancer cell line reduced cancer stem cell features and sensitized the cells to the chemotherapy drug, doxorubicin [24]. There is very little information on the role of the other EXTs in breast cancer.…”

Section: Introductionmentioning

confidence: 99%

“…Increased EXT1 mRNA expression has been found in estrogen receptor (ER)-negative breast tumors [ 22 ], whereas gene expression profiling of human breast tumor samples indicates that diminished expression of EXT1 in early-stage ER positive lymph-node negative breast cancer patients might predict an increased risk for metastasis [ 23 ]. Furthermore, overexpression of EXT1 in a non-tumorigenic epithelial cell line transformed these cells to a more malignant phenotype, whereas siRNA mediated down-regulation of EXT1 in and ER-positive breast cancer cell line reduced cancer stem cell features and sensitized the cells to the chemotherapy drug, doxorubicin [ 24 ]. There is very little information on the role of the other EXTs in breast cancer.…”

Section: Introductionmentioning

confidence: 99%

The exostosin family of glycosyltransferases: mRNA expression profiles and heparan sulphate structure in human breast carcinoma cell lines

et al. 2018

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Breast cancer remains a leading cause of cancer-related mortality in women. In recent years, regulation of genes involved in heparan sulphate (HS) biosynthesis have received increased interest as regulators of breast cancer cell adhesion and invasion. The exostosin (EXT) proteins are glycosyltransferases involved in elongation of HS, a regulator of intracellular signaling, cell–cell interactions, and tissue morphogenesis. The EXT family contains five members: EXT1, EXT2, and three EXT-like (EXTL) members: EXTL1, EXTL2, and EXTL3. While the expression levels of these enzymes change in tumor cells, little is known how this changes the structure and function of HS. In the present study, we investigated gene expression profiles of the EXT family members, their glycosyltransferase activities and HS structure in the estrogen receptor (ER), and progesterone receptor (PR) positive MCF7 cells, and the ER, PR, and human epidermal growth factor receptor-2 (HER2) negative MDA-MB-231 and HCC38 epithelial breast carcinoma cell lines. The gene expression profiles for MDA-MB-231 and HCC38 cells were very similar. In both cell lines EXTL2 was found to be up-regulated whereas EXT2 was down-regulated. Interestingly, despite having similar expression of HS elongation enzymes the two cell lines synthesized HS chains of significantly different lengths. Furthermore, both MDA-MB-231 and HCC38 exhibited markedly decreased levels of HS 6-O-sulphated disaccharides. Although the gene expression profiles of the elongation enzymes did not correlate with the length of HS chains, our results indicated specific differences in EXT enzyme levels and HS fine structure characteristic of the carcinogenic properties of the breast carcinoma cells.

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“…This was checked by suppressing EXT1 mediated by siRNA in MCF7 / ADR cells, which eliminated heparan sulphate from the cell surface. In addition, it was observed that the epithelial mesenchymal tumour was repressed and the sensitization of these cells to the action of doxorubicin was increased [39]. These findings can be used as a new vision to define EXT1 as a new therapeutic target to counteract the chemoresistance of breast cancer in breast cancer patients with therapeutic resistance based on anthracyclines [39].…”

Section: Exostosin 1 (Ext1)mentioning

confidence: 91%

“…Exostoxin 1 is a type II transmembrane glycoprotein that is regulated by the endoplasmic reticulum (ER) and is involved in the biosynthesis of heparan sulphate (HS) on the cell surface [39]. It has been identified that in MCF7 / ADR cells (doxorubicin-resistant breast cancer cell line) the EXT1 glycoprotein is highly expressed, which is reflected in an increase in EMT expression (epithelial mesenchymal transition), an overexpression of P-gp (P-glycoprotein) and with-it greater resistance to chemotherapy [39].…”

Section: Exostosin 1 (Ext1)mentioning

confidence: 99%

Genes and proteins associated with chemotherapeutic resistance in breast cancer

Linares¹,

Benítez²,

Avila³

2018

Calcified Constrictive Pericarditis Treated With Ultrasonic Devices

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Breast cancer is the main type of cancer that affects women in the world. Treatment with chemotherapeutic agents for this type of cancer depends to a large extent on the phenotypic characteristics that appear in the tumor, such as some receptors. The treatment of breast cancer is complex since not all patients respond adequately to it and this is partly due to mechanisms of resistance to treatment. The resistance either acquired or intrinsic to chemotherapeutics against breast cancer is related to multiple genes and proteins that are actively involved in the development of resistance mechanisms, which may be inhibiting the binding of the drug to the target receptor, inhibiting the gene expression of the receptors, activating signaling pathways, inducing the action of transporters that expel the drug from the cell, etc. As a result of this review, the mechanisms of chemotherapeutic resistance in breast cancer derived from genes and proteins related to say disease are described, including genes related to different types of breast cancer, as well as with different therapeutic strategies. These genes and their products of expression include a wide range of interactions and activations of signalling pathways that trigger a poor response to treatment, which translates into a worse prognosis, higher risk of prevalence and death, favouring breast cancer to be the main cause of cancer death in women. Objective: Conduct an updated review of genes and proteins, that have been associated with conferring resistance to the different chemotherapeutic agents used for the treatment of breast cancer, including the mechanism of resistance and the type of cancer in which it is generated. Method: The search for indexed articles in the PubMed (https://www.ncbi.nlm.nih.gov/pubmed/) and ScienceDirect (http://www.sciencedirect.com) databases was performed, using the words "Breast cancer resistance" as a search criterion, articles published in the period 2015-2017 were selected.

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Exostosin 1 regulates cancer cell stemness in doxorubicin-resistant breast cancer cells

Cited by 26 publications

References 53 publications

Identification of a novel glycolysis-related gene signature for predicting metastasis and survival in patients with lung adenocarcinoma

Identification of a novel glycolysis-related gene signature for predicting metastasis and survival in patients with lung adenocarcinoma

The exostosin family of glycosyltransferases: mRNA expression profiles and heparan sulphate structure in human breast carcinoma cell lines

Genes and proteins associated with chemotherapeutic resistance in breast cancer

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