TY - JOUR
T1 - AKR1B1 promotes basal-like breast cancer progression by a positive feedback loop that activates the EMT program
AU - Wu, Xuebiao
AU - Li, Xiaoli
AU - Fu, Qiang
AU - Cao, Qianhua
AU - Chen, Xingyu
AU - Wang, Mengjie
AU - Yu, Jie
AU - Long, Jingpei
AU - Yao, Jun
AU - Liu, Huixin
AU - Wang, Danping
AU - Liao, Ruocen
AU - Dong, Chenfang
N1 - Publisher Copyright:
© 2017 Wu et al.
PY - 2017/4/1
Y1 - 2017/4/1
N2 - 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 κB (NF-κB) activation. In turn, NF-κB 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.
AB - 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 κB (NF-κB) activation. In turn, NF-κB 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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U2 - 10.1084/jem.20160903
DO - 10.1084/jem.20160903
M3 - Article
C2 - 28270406
AN - SCOPUS:85021941759
SN - 0022-1007
VL - 214
SP - 1065
EP - 1079
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 4
ER -