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

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.

• Authors: Xuebiao Wu, Xiaoli Li, Qiang Fu, Qianhua Cao, Xingyu Chen, Mengjie Wang, Jie Yu, Jingpei Long, Jun Yao, Huixin Liu, Danping Wang, Ruocen Liao, Chenfang Dong
• Journal: The Journal of experimental medicine (J Exp Med) Vol. 214 Issue 4 Pg. 1065-1079 (04 03 2017) ISSN: 1540-9538 [Electronic] United States
• PMID: 28270406 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2017 Wu et al.

Chemical References

• NF-kappa B
• RELA protein, human
• Transcription Factor RelA
• Twist-Related Protein 2
• Dinoprost
• AKR1B1 protein, human
• Aldehyde Reductase

Topics

• Aldehyde Reductase (antagonists & inhibitors, physiology)
• Animals
• Breast Neoplasms (drug therapy, etiology, pathology)
• Cell Line, Tumor
• Cell Movement
• Dinoprost (analysis)
• Disease Progression
• Epithelial-Mesenchymal Transition
• Feedback, Physiological
• Female
• Humans
• Mice
• NF-kappa B (physiology)
• Neoplasm Invasiveness
• Neoplastic Stem Cells (pathology)
• Transcription Factor RelA (physiology)
• Twist-Related Protein 2 (physiology)