AKR1B1 promotes basal-like breast cancer progression by a positive feedback loop that activates the EMT program.
AKR1B1 promotes basal-like breast cancer progression by a positive feedback loop that activates the EMT program.
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AKR1B1 通过激活 EMT 程序的正反馈环促进基底样乳腺癌进展
DOI：
10.1084/jem.20160903
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发表时间：
2017-04-03
期刊：
影响因子：
--
通讯作者：
Dong C
中科院分区：
文献类型：
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作者：
Wu X;Li X;Fu Q;Cao Q;Chen X;Wang M;Yu J;Long J;Yao J;Liu H;Wang D;Liao R;Dong C
BLBC的治疗代表了未满足的医疗需求。Wu等人的研究表明，AKR1B1通过激活EMT程序的正反馈循环促进BLBC的进展，这表明抑制AKR1B1有可能成为BLBC的一种有价值的治疗策略。基底样乳腺癌（BLBC）与高度、远处转移和预后不良相关。阐明BLBC侵袭性的决定因素可能有助于开发针对这种具有挑战性疾病的新干预措施。在本研究中，我们发现aldo-酮还原酶1成员B1 （AKR1B1）过表达与乳腺癌患者BLBC高度相关，并预测预后不良。机制上，Twist2转录诱导AKR1B1表达，导致核因子κB （NF-κB）活化。反过来，NF-κB上调Twist2的表达，从而实现一个正反馈回路，激活上皮-间质转化程序，增强BLBC中癌症干细胞（CSC）样特性。AKR1B1表达促进肿瘤发生和转移，而AKR1B1敲低抑制。重要的是，伊帕司他是一种AKR1B1抑制剂，已被批准用于治疗糖尿病并发症，可显著抑制CSC特性、致瘤性和BLBC细胞的转移。总之，我们的研究确定了AKR1B1是肿瘤侵袭性的关键调节剂，并表明AKR1B1的药物抑制有可能成为BLBC的一种有价值的治疗策略。
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.