Research Papers:

HIF2α/EFEMP1 cascade mediates hypoxic effects on breast cancer stem cell hierarchy

Ji-Hye Kwak, Na-Hee Lee, Hwa-Yong Lee, In-Sun Hong and Jeong-Seok Nam _

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Oncotarget. 2016; 7:43518-43533. https://doi.org/10.18632/oncotarget.9846

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Ji-Hye Kwak1,2,*, Na-Hee Lee1,2,*, Hwa-Yong Lee3,*, In-Sun Hong1,2, Jeong-Seok Nam4

1Laboratory of Stem Cell Research, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, 406-840, Republic of Korea

2Department of Molecular Medicine, School of Medicine, Gachon University, Incheon, 406-840, Republic of Korea

3The Faculty of Liberal Arts, Jungwon University, Chungbuk, 367-805, Republic of Korea

4School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, 500-712, Republic of Korea

*The authors contributed equally to this work

Correspondence to:

Jeong-Seok Nam, email: namje@gist.ac.kr

In-Sun Hong, email: hongstem@gachon.ac.kr

Keywords: breast cancer cancer stem cells, hypoxia, HIF2α, EFEMP1

Received: March 14, 2016     Accepted: May 05, 2016     Published: June 06, 2016


Breast cancer stem cells (BCSCs) have been shown to contribute to tumor growth, metastasis, and recurrence. They are also markedly resistant to conventional cancer treatments, such as chemotherapy and radiation. Recent studies have suggested that hypoxia is one of the prominent micro-environmental factors that increase the self-renewal ability of BCSCs, partially by enhancing CSC phenotypes. Thus, the identification and development of new therapeutic approaches based on targeting the hypoxia-dependent responses in BCSCs is urgent. Through various in vitro studies, we found that hypoxia specifically up-regulates BCSC sphere formation and a subset of CD44+/CD24−/low CSCs. Hypoxia inducible factors 2α (HIF2α) depletion suppressed CSC-like phenotypes and CSC-mediated drug resistance in breast cancer. Furthermore, the stimulatory effects of hypoxia-induced HIF2α on BCSC sphere formation were successfully attenuated by epidermal growth factor-containing fibulin-like extracellular matrix protein 1 (EFEMP1) knockdown. Taken together, these data suggest that HIF2α mediates hypoxia-induced cancer growth/metastasis and that EFEMP1 is a downstream effector of hypoxia-induced HIF2α during breast tumorigenesis.

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