期刊
JOURNAL OF EXPERIMENTAL MEDICINE
卷 214, 期 4, 页码 1065-1079出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20160903
关键词
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资金
- National Natural Science Foundation of China [81472455, 81370730, 81571512]
- Natural Science Foundation of Zhejiang Province [LZ17H160002]
- Major Research Development Program of China [2016YFC1303200]
- Natural Science Foundation of Shandong Province [ZR2015JL027]
- Fundamental Research Funds for Central Universities of China
- Thousand Young Talents Plan of China
Basal-like breast cancer (BLBC) is associated with high-grade, distant metastasis and poor prognosis. Elucidating the determinants of aggressiveness in BLBC may facilitate the development of novel interventions for this challenging disease. In this study, we show that aldo-keto reductase 1 member B1 (AKR1B1) overexpression highly correlates with BLBC and predicts poor prognosis in breast cancer patients. Mechanistically, Twist2 transcriptionally induces AKR1B1 expression, leading to nuclear factor kappa B (NF-kappa B) activation. In turn, NF-kappa B up-regulates Twist2 expression, thereby fulfilling a positive feedback loop that activates the epithelial-mesenchymal transition program and enhances cancer stem cell (CSC)-like properties in BLBC. AKR1B1 expression promotes, whereas AKR1B1 knockdown inhibits, tumorigenicity and metastasis. Importantly, epalrestat, an AKR1B1 inhibitor that has been approved for the treatment of diabetic complications, significantly suppresses CSC properties, tumorigenicity, and metastasis of BLBC cells. Together, our study identifies AKR1B1 as a key modulator of tumor aggressiveness and suggests that pharmacologic inhibition of AKR1B1 has the potential to become a valuable therapeutic strategy for BLBC.
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