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

2017 ◽  
Vol 214 (4) ◽  
pp. 1065-1079 ◽  
Author(s):  
Xuebiao Wu ◽  
Xiaoli Li ◽  
Qiang Fu ◽  
Qianhua Cao ◽  
Xingyu Chen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Positive Feedback ◽  
Poor Prognosis ◽  
Feedback Loop ◽  
Epithelial Mesenchymal Transition ◽  
Breast Cancer Patients ◽  
Positive Feedback Loop ◽  
Mesenchymal Transition ◽  
Basal Like Breast Cancer

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.

scholarly journals Persistent activation of STAT 3 by PIM 2‐driven positive feedback loop for epithelial‐mesenchymal transition in breast cancer

2015 ◽  
Vol 106 (6) ◽  
pp. 718-725 ◽  
Author(s):  
Nizam Uddin ◽  
Rae‐Kwon Kim ◽  
Ki‐Chun Yoo ◽  
Young‐Heon Kim ◽  
Yan‐Hong Cui ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Positive Feedback ◽  
Feedback Loop ◽  
Epithelial Mesenchymal Transition ◽  
Positive Feedback Loop ◽  
Mesenchymal Transition

scholarly journals A theoretical approach to coupling the epithelial-mesenchymal transition (EMT) to extracellular matrix (ECM) stiffness via LOXL2

2021 ◽  
Author(s):  
Youyuan Deng ◽  
Priyanka Chakraborty ◽  
Mohit Kumar Jolly ◽  
Herbert Levine
Keyword(s):  
Extracellular Matrix ◽  
Cancer Progression ◽  
Positive Feedback ◽  
Feedback Loop ◽  
Epithelial Mesenchymal Transition ◽  
Critical Role ◽  
Cross Linking ◽  
Positive Feedback Loop ◽  
Mesenchymal Transition ◽  
The Impact

AbstractThe epithelial-mesenchymal transition (EMT) plays a critical role in cancer progression, being responsible in many cases for the onset of the metastatic cascade and being integral in the ability of cells to resist drug treatment. Most studies of EMT focus on its induction via chemical signals such as TGF-β or Notch ligands, but it has become increasingly clear that biomechanical features of the microenvironment such as ECM (extracellular matrix) stiffness can be equally important. Here, we introduce a coupled feedback loop connecting stiffness to the EMT transcription factor ZEB1, which acts via increasing the secretion of LOXL2 that leads to increased cross-linking of collagen fibers in the ECM. This increased cross-linking can effectively increase ECM stiffness and increase ZEB1 levels, thus setting a positive feedback loop between ZEB1 and ECM stiffness. To investigate the impact of this non-cell-autonomous effect, we introduce a computational approach capable of connecting LOXL2 concentration to increased stiffness and thereby to higher ZEB1 levels. Our results indicate that this positive feedback loop, once activated, can effectively lock the cells in a mesenchymal state.

scholarly journals A Theoretical Approach to Coupling the Epithelial-Mesenchymal Transition (EMT) to Extracellular Matrix (ECM) Stiffness via LOXL2

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1609
Author(s):  
Youyuan Deng ◽  
Priyanka Chakraborty ◽  
Mohit Kumar Jolly ◽  
Herbert Levine
Keyword(s):  
Extracellular Matrix ◽  
Cancer Progression ◽  
Positive Feedback ◽  
Feedback Loop ◽  
Epithelial Mesenchymal Transition ◽  
Critical Role ◽  
Cross Linking ◽  
Positive Feedback Loop ◽  
Mesenchymal Transition ◽  
The Impact

The epithelial-mesenchymal transition (EMT) plays a critical role in cancer progression, being responsible in many cases for the onset of the metastatic cascade and being integral in the ability of cells to resist drug treatment. Most studies of EMT focus on its induction via chemical signals such as TGF-β or Notch ligands, but it has become increasingly clear that biomechanical features of the microenvironment such as extracellular matrix (ECM) stiffness can be equally important. Here, we introduce a coupled feedback loop connecting stiffness to the EMT transcription factor ZEB1, which acts via increasing the secretion of LOXL2 that leads to increased cross-linking of collagen fibers in the ECM. This increased cross-linking can effectively increase ECM stiffness and increase ZEB1 levels, thus setting a positive feedback loop between ZEB1 and ECM stiffness. To investigate the impact of this non-cell-autonomous effect, we introduce a computational approach capable of connecting LOXL2 concentration to increased stiffness and thereby to higher ZEB1 levels. Our results indicate that this positive feedback loop, once activated, can effectively lock the cells in a mesenchymal state. The spatial-temporal heterogeneity of the LOXL2 concentration and thus the mechanical stiffness also has direct implications for migrating cells that attempt to escape the primary tumor.

scholarly journals Twist-mediated PAR1 induction is required for breast cancer progression and metastasis by inhibiting Hippo pathway

2020 ◽  
Vol 11 (7) ◽  
Author(s):  
Yifan Wang ◽  
Ruocen Liao ◽  
Xingyu Chen ◽  
Xuhua Ying ◽  
Guanping Chen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Invasive Breast Cancer ◽  
Breast Cancer Cells ◽  
Epithelial Mesenchymal Transition ◽  
Hippo Pathway ◽  
Breast Cancer Patients ◽  
Mesenchymal Transition

Abstract Breast cancer is considered to be the most prevalent cancer in women worldwide, and metastasis is the primary cause of death. Protease-activated receptor 1 (PAR1) is a GPCR family member involved in the invasive and metastatic processes of cancer cells. However, the functions and underlying mechanisms of PAR1 in breast cancer remain unclear. In this study, we found that PAR1 is highly expressed in high invasive breast cancer cells, and predicts poor prognosis in ER-negative and high-grade breast cancer patients. Mechanistically, Twist transcriptionally induces PAR1 expression, leading to inhibition of Hippo pathway and activation of YAP/TAZ; Inhibition of PAR1 suppresses YAP/TAZ-induced epithelial-mesenchymal transition (EMT), invasion, migration, cancer stem cell (CSC)-like properties, tumor growth and metastasis of breast cancer cells in vitro and in vivo. These findings suggest that PAR1 acts as a direct transcriptionally target of Twist, can promote EMT, tumorigenicity and metastasis by controlling the Hippo pathway; this may lead to a potential therapeutic target for treating invasive breast cancer.

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