AKR1B1 promotes basal-like breast cancer progression by a positive feedback loop that activates the EMT program
| Autor: | Jingpei Long, Qiang Fu, Qianhua Cao, Chenfang Dong, Ruocen Liao, Huixin Liu, Xiaoli Li, Mengjie Wang, Jun Yao, Danping Wang, Xingyu Chen, Xuebiao Wu, Jie Yu |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Epithelial-Mesenchymal Transition Immunology Breast Neoplasms Disease Biology Dinoprost Article Metastasis 03 medical and health sciences chemistry.chemical_compound Mice 0302 clinical medicine Breast cancer Cancer stem cell Aldehyde Reductase Cell Movement Cell Line Tumor medicine Immunology and Allergy Animals Humans Neoplasm Invasiveness Epithelial–mesenchymal transition Epalrestat Research Articles Feedback Physiological Gene knockdown NF-kappa B Transcription Factor RelA Twist-Related Protein 2 medicine.disease 030104 developmental biology chemistry Cell culture 030220 oncology & carcinogenesis Cancer research Disease Progression Neoplastic Stem Cells Female |
| Zdroj: | The Journal of Experimental Medicine |
| ISSN: | 1540-9538 0022-1007 |
| Popis: | The treatment of BLBC represents an unmet medical need. Wu et al. show that AKR1B1 facilitates BLBC progression through a positive feedback loop that activates the EMT program, suggesting that inhibition of AKR1B1 has the potential to become a valuable therapeutic strategy for BLBC. 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. |
| Databáze: | OpenAIRE |
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