Radioresistant breast cancer cells exhibit increased resistance to chemotherapy and enhanced invasive properties due to cancer stem cells

Ko,Young Shin; Jin,Hana; Lee,Jong Sil; Park,Sang Won; Chang,Ki Churl; Kang,Ki Mun; Jeong,Bae Kwon; Kim,Hye Jung

doi:10.3892/or.2018.6714

Radioresistant breast cancer cells exhibit increased resistance to chemotherapy and enhanced invasive properties due to cancer stem cells

Authors:
- Young Shin Ko
- Hana Jin
- Jong Sil Lee
- Sang Won Park
- Ki Churl Chang
- Ki Mun Kang
- Bae Kwon Jeong
- Hye Jung Kim
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Affiliations: Department of Pharmacology, School of Medicine, Institute of Health Sciences, Gyeongsang National University, Jinju 52727, Republic of Korea, Department of Pathology, School of Medicine, Institute of Health Sciences, Gyeongsang National University, Jinju 52727, Republic of Korea, Department of Radiation Oncology, School of Medicine, Institute of Health Sciences, Gyeongsang National University, Jinju 52727, Republic of Korea
Published online on: September 18, 2018 https://doi.org/10.3892/or.2018.6714
Pages: 3752-3762

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Abstract

Previous studies suggest that cancer stem cells (CSCs) exist in solid tumors, and contribute to therapeutic resistance and disease recurrence. Therefore, the present study aimed to investigate whether radioresistant (RT‑R) breast cancer cells derived from breast cancer cells increase the number of CSCs, and whether these CSCs are responsible to increased invasiveness and therapeutic resistance. MCF‑7, T47D and MDA‑MB‑231 cells were irradiated 25 times (2 Gy each; 50 Gy total) to generate radioresistant breast cancer cells (RT‑R‑MCF‑7, RT‑R‑T47D and RT‑R‑MDA‑MB‑231). RT‑R‑breast cancer cells demonstrated increased cell viability against irradiation and increased colony forming abilities compared with parental breast cancer cells. Particularly, RT‑R‑MDA‑MB‑231 cells derived from highly metastatic MDA‑MB‑231 cells exhibited most radioresistance and chemoresistance of the three cell lines. In addition, MDA‑MB‑231 cells exhibited the most increased protein levels of CSCs markers cluster of differentiation 44, Notch‑4, octamer‑binding transcription factor 3/4 and aldehyde dehydrogenase 1, compared with RT‑R‑MCF‑7 cells, suggesting highly metastatic breast cancer cells MDA‑MB‑231 produce more CSCs. RT‑R‑MDA‑MB‑231 cells increased intercellular adhesion molecule‑1 and vascular cell adhesion molecule‑1 levels, resulting in enhanced migration and adhesion to endothelial cells (ECs), and enhanced invasiveness through ECs by inducing matrix metalloproteinase‑9, Snail‑1 and β‑catenin, and by downregulating E‑cadherin compared with MDA‑MB‑231 cells. These results suggest that highly metastatic breast cancer cells may increase the number of CSCs following radiation therapy, and CSCs present in RT‑R‑MDA‑MB‑231 cells contribute to the enhanced invasiveness by increasing migration, adhesion to ECs and invasion through ECs by promoting epithelial‑mesenchymal transition (EMT) via the upregulation of adhesion molecules and EMT‑associated proteins.

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