HIF2α/EFEMP1 cascade mediates hypoxic effects on breast cancer stem cell hierarchy.
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.
Laboratory of Stem Cell Research, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, 406-840, Republic of Korea.|Department of Molecular Medicine, School of Medicine, Gachon University, Incheon, 406-840, Republic of Korea.
Ji-Hye
JH
Kwak
Laboratory of Stem Cell Research, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, 406-840, Republic of Korea.|Department of Molecular Medicine, School of Medicine, Gachon University, Incheon, 406-840, Republic of Korea.
Na-Hee
NH
Lee
The Faculty of Liberal Arts, Jungwon University, Chungbuk, 367-805, Republic of Korea.
Hwa-Yong
HY
Lee
Laboratory of Stem Cell Research, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, 406-840, Republic of Korea.|Department of Molecular Medicine, School of Medicine, Gachon University, Incheon, 406-840, Republic of Korea.
In-Sun
IS
Hong
School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, 500-712, Republic of Korea.
Jeong-Seok
JS
Nam
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D001943:Breast Neoplasms / Q000503:physiopathology*; D051927:CD24 Antigen / Q000378:metabolism; D063646:Carcinogenesis / Q000378:metabolism*; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D055785:Gene Knockdown Techniques; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009364:Neoplasm Recurrence, Local; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D018874:Spheroids, Cellular / Q000378:metabolism / Q000473:pathology; D023041:Xenograft Model Antitumor Assays; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D051927:CD24 Antigen; D016326:Extracellular Matrix Proteins; D018960:Hyaluronan Receptors; D034741:RNA, Small Interfering; D000099162:Endothelial PAS Domain-Containing Protein 1; C497889:CD24 protein, human; C497483:CD44 protein, human; C119630:EFEMP1 protein, human
EFEMP1; HIF2α; breast cancer cancer stem cells; hypoxia