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J Exp Med. 2017 Apr 3;214(4):1065-1079. doi: 10.1084/jem.20160903. Epub 2017 Mar 7.

AKR1B1 promotes basal-like breast cancer progression by a positive feedback loop that activates the EMT program.

Wu X1,2, Li X1,2, Fu Q3, Cao Q1,2, Chen X1,2, Wang M1,2, Yu J1,2, Long J4, Yao J5, Liu H1,2, Wang D1,2, Liao R1,2, Dong C6,2.

Author information

1
Department of Pathology and Pathophysiology, Zhejiang University School of Medicine, Hangzhou 310058, China.
2
Zhejiang Key Laboratory for Disease Proteomics, Zhejiang University School of Medicine, Hangzhou 310058, China.
3
Department of Immunology, Binzhou Medical University, Yantai 264003, China.
4
Department of Breast Surgery, Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China.
5
Department of Neuro-oncology, M.D. Anderson Cancer Center, The University of Texas, Houston, TX 77030.
6
Department of Pathology and Pathophysiology, Zhejiang University School of Medicine, Hangzhou 310058, China chenfangdong@zju.edu.cn.

Abstract

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.

PMID:
28270406
PMCID:
PMC5379972
DOI:
10.1084/jem.20160903
[Indexed for MEDLINE]
Free PMC Article

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