title: 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.affiliation: Department of Pathology and Pathophysiology, Zhejiang University School of Medicine, Hangzhou 310058, China.|Zhejiang Key Laboratory for Disease Proteomics, Zhejiang University School of Medicine, Hangzhou 310058, China.
authors.forename: Xuebiao
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Pathology and Pathophysiology, Zhejiang University School of Medicine, Hangzhou 310058, China.|Zhejiang Key Laboratory for Disease Proteomics, Zhejiang University School of Medicine, Hangzhou 310058, China.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Immunology, Binzhou Medical University, Yantai 264003, China.
authors.forename: Qiang
authors.identifier: 0000-0002-6932-7103
authors.initials: Q
authors.lastname: Fu
authors.affiliation: Department of Pathology and Pathophysiology, Zhejiang University School of Medicine, Hangzhou 310058, China.|Zhejiang Key Laboratory for Disease Proteomics, Zhejiang University School of Medicine, Hangzhou 310058, China.
authors.forename: Qianhua
authors.initials: Q
authors.lastname: Cao
authors.affiliation: Department of Pathology and Pathophysiology, Zhejiang University School of Medicine, Hangzhou 310058, China.|Zhejiang Key Laboratory for Disease Proteomics, Zhejiang University School of Medicine, Hangzhou 310058, China.
authors.forename: Xingyu
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Pathology and Pathophysiology, Zhejiang University School of Medicine, Hangzhou 310058, China.|Zhejiang Key Laboratory for Disease Proteomics, Zhejiang University School of Medicine, Hangzhou 310058, China.
authors.forename: Mengjie
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Pathology and Pathophysiology, Zhejiang University School of Medicine, Hangzhou 310058, China.|Zhejiang Key Laboratory for Disease Proteomics, Zhejiang University School of Medicine, Hangzhou 310058, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Yu
authors.affiliation: Department of Breast Surgery, Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China.
authors.forename: Jingpei
authors.initials: J
authors.lastname: Long
authors.affiliation: Department of Neuro-oncology, M.D. Anderson Cancer Center, The University of Texas, Houston, TX 77030.
authors.forename: Jun
authors.initials: J
authors.lastname: Yao
authors.affiliation: Department of Pathology and Pathophysiology, Zhejiang University School of Medicine, Hangzhou 310058, China.|Zhejiang Key Laboratory for Disease Proteomics, Zhejiang University School of Medicine, Hangzhou 310058, China.
authors.forename: Huixin
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Pathology and Pathophysiology, Zhejiang University School of Medicine, Hangzhou 310058, China.|Zhejiang Key Laboratory for Disease Proteomics, Zhejiang University School of Medicine, Hangzhou 310058, China.
authors.forename: Danping
authors.identifier: 0000-0001-7555-038X
authors.initials: D
authors.lastname: Wang
authors.affiliation: Department of Pathology and Pathophysiology, Zhejiang University School of Medicine, Hangzhou 310058, China.|Zhejiang Key Laboratory for Disease Proteomics, Zhejiang University School of Medicine, Hangzhou 310058, China.
authors.forename: Ruocen
authors.initials: R
authors.lastname: Liao
authors.affiliation: Department of Pathology and Pathophysiology, Zhejiang University School of Medicine, Hangzhou 310058, China chenfangdong@zju.edu.cn.|Zhejiang Key Laboratory for Disease Proteomics, Zhejiang University School of Medicine, Hangzhou 310058, China.
authors.forename: Chenfang
authors.identifier: 0000-0003-2964-5876
authors.initials: C
authors.lastname: Dong
mesh_terms: D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors / Q000502:physiology*; D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy / Q000209:etiology / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D015237:Dinoprost / Q000032:analysis; D018450:Disease Progression; D058750:Epithelial-Mesenchymal Transition; D025461:Feedback, Physiological; D005260:Female; D006801:Humans; D051379:Mice; D016328:NF-kappa B / Q000502:physiology; D009361:Neoplasm Invasiveness; D014411:Neoplastic Stem Cells / Q000473:pathology; D051996:Transcription Factor RelA / Q000502:physiology; D000071417:Twist-Related Protein 2 / Q000502:physiology
chemical_list: D016328:NF-kappa B; C498143:RELA protein, human; D051996:Transcription Factor RelA; D000071417:Twist-Related Protein 2; D015237:Dinoprost; C484670:AKR1B1 protein, human; D000449:Aldehyde Reductase