LEF1 supports metastatic brain colonization by regulating glutathione metabolism and increasing ROS resistance in breast cancer

Blazquez, Raquel; Rietkötter, Eva; Wenske, Britta; Wlochowitz, Darius; Sparrer, Daniela; Vollmer, Elena; Müller, G.; Seegerer, Julia; Sun, Xueni; Dettmer, Katja; Barrantes‐Freer, Alonso; Stange, Lena; Utpatel, Kirsten; Bleckmann, Annalen; Treiber, Hannes; Bohnenberger, Hanibal; Lenz, Christof; Schulz, Matthias; Reimelt, Christian; Hackl, Christina; Grade, Marian; Büyüktaş, Deram; Siam, Laila; Balkenhol, Marko; Stadelmann, Christine; Kube, Dieter; Krahn, Michael P.; Proescholdt, Martin; Riemenschneider, Markus J.; Evert, Matthias; Oefner, Peter J.; Hanisch, Uwe; Binder, Claudia R.; Pukrop, Tobias

doi:10.1002/ijc.32742

Cited by 29 publications

(15 citation statements)

References 45 publications

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“…LSD1 (lysine-specific demethylase 1) promotes bladder cancer progression by upregulating LEF1 and enhancing EMT [ 9 ]. LEF1 expression may contribute to cancer development [ 26 , 27 , 28 ], but there is a lack of evidence to support malignant phenotype changes, especially motility-associated microstructure changes, such as remodeling of lamellipodia/filopodia based on F-actin/β-tubulin polymerization.…”

Section: Discussionmentioning

confidence: 99%

LEF1 Enhances the Progression of Colonic Adenocarcinoma via Remodeling the Cell Motility Associated Structures

Zhang

et al. 2021

IJMS

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Lymphoid enhancer-binding factor 1 (LEF1) is a key transcription factor mediating the Wnt signaling pathway. LEF1 is a regulator that is closely associated with tumor malignancy and is usually upregulated in cancers, including colonic adenocarcinoma. The underlying molecular mechanisms of LEF1 regulation for colonic adenocarcinoma progression remain unknown. To explore it, the LEF1 expression in caco2 cells was inhibited using an shRNA approach. The results showed that downregulation of LEF1 inhibited the malignancy and motility associated microstructures, such as polymerization of F-actin, β-tubulin, and Lamin B1 in caco2 cells. LEF1 inhibition suppressed the expression of epithelial/endothelial-mesenchymal transition (EMT) relevant genes. Overall, the current results demonstrated that LEF1 plays a pivotal role in maintaining the malignancy of colonic adenocarcinoma by remodeling motility correlated microstructures and suppressing the expression of EMT-relevant genes. Our study provided evidence of the roles LEF1 played in colonic adenocarcinoma progression, and suggest LEF1 as a potential target for colonic adenocarcinoma therapy.

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Section: Discussionmentioning

confidence: 99%

LEF1 Enhances the Progression of Colonic Adenocarcinoma via Remodeling the Cell Motility Associated Structures

Zhang

et al. 2021

IJMS

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“…LEF1 is a transcription factor that promotes the canonical Wnt/β-catenin signaling pathway by cooperating with TCF4 and is pathologically involved in cancer development and progression in multiple cancer types [14]. Previous studies have shown that ectopic LEF1 expression enhances the expression of epithelial-mesenchymal transition (EMT)-related genes, including the epithelial marker E-cadherin and mesenchymal markers N-cadherin, vimentin, ZEB1, and SNAIL, which are involved in cancer metastasis [15,16]. Thus, LEF1 is a promising molecular target for cancer treatment.…”

Section: Introductionmentioning

confidence: 99%

Cinobufagin Suppresses Melanoma Cell Growth by Inhibiting LEF1

Kim

Fang

Lim

et al. 2020

IJMS

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Constitutive activation of the β-catenin dependent canonical Wnt signaling pathway, which enhances tumor growth and progression in multiple types of cancer, is commonly observed in melanoma. LEF1 activates β-catenin/TCF4 transcriptional activity, promoting tumor growth and progression. Although several reports have shown that LEF1 is highly expressed in melanoma, the functional role of LEF1 in melanoma growth is not fully understood. While A375, A2058, and G361 melanoma cells exhibit abnormally high LEF1 expression, lung cancer cells express lower LEF1 levels. A luciferase assay-based high throughput screening (HTS) with a natural compound library showed that cinobufagin suppressed β-catenin/TCF4 transcriptional activity by inhibiting LEF1 expression. Cinobufagin decreases LEF1 expression in a dose-dependent manner and Wnt/β-catenin target genes such as Axin-2, cyclin D1, and c-Myc in melanoma cell lines. Cinobufagin sensitively attenuates cell viability and induces apoptosis in LEF1 expressing melanoma cells compared to LEF1-low expressing lung cancer cells. In addition, ectopic LEF1 expression is sufficient to attenuate cinobufagin-induced apoptosis and cell growth retardation in melanoma cells. Thus, we suggest that cinobufagin is a potential anti-melanoma drug that suppresses tumor-promoting Wnt/β-catenin signaling via LEF1 inhibition.

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“…These Wnt target genes ( LEF1 and TCF4 ) and YAP ( BIRC5 and ANKRD1 ) target genes have been commonly used in the breast cancer field and are key to the activation of two signaling pathways. [8a,21] In addition, LEF‐1 was also found to support metastatic brain colonization in breast cancer and associated with survival and metastases in chemoresistant TNBC; [ 22 ] YAP target genes BIRC5 promotes proliferation of TNBC cells, and ANKRD1 mediates the growth of breast cancer cells including TNBC cells. [ 23 ] These results suggest a close association between Wnt/YAP signaling, ALDH+ CSCs, and patient survival.…”

Section: Resultsmentioning

confidence: 99%

Nanoparticles Loaded with Wnt and YAP/Mevalonate Inhibitors in Combination with Paclitaxel Stop the Growth of TNBC Patient‐Derived Xenografts and Diminish Tumorigenesis

Sulaiman

McGarry

El-Sahli

et al. 2020

Advanced Therapeutics

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Triple negative breast cancer (TNBC) accounts for the majority of breast cancer‐related deaths and remains the hardest breast cancer to treat due to the lack of specific therapeutic targets. While chemotherapy is the mainstay of systemic treatment for TNBC, it is associated with chemotherapy‐induced cancer stem cells (CSCs) and tumor regeneration. Here, it is found that Wnt and YAP target genes that have been closely associated with CSCs are highly expressed in TNBC patient tumors and negatively correlated with patient survival. Therefore, a nanotherapeutic strategy is employed, using nanomaterials that are approved by the FDA, and two co‐delivery nanoparticle platforms (NPs) are developed to target TNBC. These NPs contain Wnt inhibitor PRI‐724 (in clinical trials) and YAP/mevalonate inhibitor simvastatin (FDA‐approved). Toward clinical translation, nanotherapeutic efficacy is assessed in clinically relevant patient‐derived xenograft (PDX) models. These NPs in combination with the chemotherapeutic drug paclitaxel effectively halt the growth of both paclitaxel‐resistant and paclitaxel‐sensitive PDX tumors, and diminish the paclitaxel‐induced CSC enrichment around two to fourfold. Importantly, NPs also decrease the paclitaxel‐enhanced PDX tumorigenesis after secondary transplantation. Together, this study demonstrates the efficacy of two NP platforms using clinically translatable TNBC PDX models, suggesting their application potential for the treatment of TNBC.

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LEF1 supports metastatic brain colonization by regulating glutathione metabolism and increasing ROS resistance in breast cancer

Cited by 29 publications

References 45 publications

LEF1 Enhances the Progression of Colonic Adenocarcinoma via Remodeling the Cell Motility Associated Structures

LEF1 Enhances the Progression of Colonic Adenocarcinoma via Remodeling the Cell Motility Associated Structures

Cinobufagin Suppresses Melanoma Cell Growth by Inhibiting LEF1

Nanoparticles Loaded with Wnt and YAP/Mevalonate Inhibitors in Combination with Paclitaxel Stop the Growth of TNBC Patient‐Derived Xenografts and Diminish Tumorigenesis

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