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

Sarala Manandhar; Chang-Gu Kim; Sun-Hee Lee; Soo Hyun Kang; Nikita Basnet; You Mie Lee

doi:10.18632/oncotarget.19737

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Research Papers:

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

Sarala Manandhar, Chang-Gu Kim, Sun-Hee Lee, Soo Hyun Kang, Nikita Basnet and You Mie Lee _

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Oncotarget. 2017; 8:70521-70537. https://doi.org/10.18632/oncotarget.19737

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Abstract

Sarala Manandhar1, Chang-Gu Kim1, Sun-Hee Lee1, Soo Hyun Kang1, Nikita Basnet1 and You Mie Lee1

1BK21 Plus Multi-Omics Based Creative Drug Research Training Team (22A20154413076), National Basic Research Laboratory of Vascular Homeostasis Regulation, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, Daegu 41566, South Korea

Correspondence to:

You Mie Lee, email: [email protected]

Keywords: breast cancer, cancer stem cell, exostosin1, ALDH⁺, CD44⁺/CD24^-

Received: October 15, 2016 Accepted: June 26, 2017 Published: July 31, 2017

ABSTRACT

Cancer stem cells (CSCs) are associated with cancer recurrence following radio/chemotherapy owing to their high resistance to therapeutic intervention. In this study, we investigated the role of exostoxin 1 (EXT1), an endoplasmic reticulum (ER)-residing type II transmembrane glycoprotein, in cancer cell stemness. DNA microarray analysis revealed that doxorubicin-resistant MCF7/ADR cells have high levels of EXT1 expression compared to its parental cell line, MCF7. These cells showed significantly higher populations of CSCs and larger populations of aldehyde dehydrogenase (ALDH⁺) and CD44⁺/CD24^-cells, as compared to MCF7 cells. siRNA-mediated knockdown of EXT1 in MCF7/ADR cells significantly reduced cancer stem cell markers, populations of ALDH⁺and CD44⁺/CD24^- cells, mRNA and protein expression for CD44, and mammosphere number. Furthermore, epithelial mesenchymal transition (EMT) markers and migratory behavior were also repressed with reduced EXT1. In an in vitro soft agar colony formation assay, EXT1 knockdown by short hairpin RNA (shRNA) reduced the colony formation ability of these cells. Based on these results, we suggest that EXT1 could be a promising novel target to overcome cancer cell stemness in anthracycline-based therapeutic resistance.

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Research Papers:

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

Abstract