Targeting the Hippo Pathway for Breast Cancer Therapy

Wu, Liqing; Yang, Xiaolong

doi:10.3390/cancers10110422

Cited by 89 publications

(76 citation statements)

References 139 publications

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“…In fact, our study identified for the first time CYLD as a negative regulator of the YAP/TAZ transcriptional regulators in confluent culture conditions. Hyperactivation of the YAP/TAZ complex has previously been involved in the progression of breast cancer by promoting migration and invasion [51]. Our analysis indicates that one of the molecular alterations that can induce the activity of these transcription factors in mammary epithelial cells is the downregulation of CYLD.…”

Section: Discussionmentioning

confidence: 53%

The Tumor Suppressor CYLD Inhibits Mammary Epithelial to Mesenchymal Transition by the Coordinated Inhibition of YAP/TAZ and TGFβ Signaling

Pseftogas

Xanthopoulos

Poutahidis

et al. 2020

Cancers

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Downregulation of the cylindromatosis (CYLD) tumor suppressor has been associated with breast cancer development and progression. Here, we report a critical role for CYLD in maintaining the phenotype of mammary epithelial cells in vitro and in vivo. CYLD downregulation or inactivation induced an epithelial to mesenchymal transition of mammary epithelial cells that was dependent on the concomitant activation of the transcription factors Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) and transforming growth factor beta (TGFβ)signaling. CYLD inactivation enhanced the nuclear localization of YAP/TAZ and the phosphorylation of Small Mothers Against Decapentaplegic (SMAD)2/3 proteins in confluent cell culture conditions. Consistent with these findings were the hyperplastic alterations of CYLD-deficient mouse mammary epithelia, which were associated with enhanced nuclear expression of the YAP/TAZ transcription factors. Furthermore, in human breast cancer samples, downregulation of CYLD expression correlates with enhanced YAP/TAZ-regulated target gene expression. Our results identify CYLD as a critical regulator of a signaling node that prevents the coordinated activation of YAP/TAZ and the TGFβ pathway in mammary epithelial cells, in order to maintain their phenotypic identity and homeostasis. Consequently, they provide a novel conceptual framework that supports and explains a causal implication of deficient CYLD expression in aggressive human breast cancers.

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Section: Discussionmentioning

confidence: 53%

The Tumor Suppressor CYLD Inhibits Mammary Epithelial to Mesenchymal Transition by the Coordinated Inhibition of YAP/TAZ and TGFβ Signaling

Pseftogas

Xanthopoulos

Poutahidis

et al. 2020

Cancers

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“…The Hippo pathway plays important roles in tumor suppression and immune response. However, alterations in this pathway are involved in the BC tumorigenesis and metastasis 85 . Lastly, the thyroid hormone pathway plays an important role as regulator of growth and metabolism.…”

Section: Discussionmentioning

confidence: 99%

OncoOmics approaches to reveal essential genes in breast cancer: a panoramic view from pathogenesis to precision medicine

López‐Cortés

Paz‐y‐Miño

Guerrero

et al. 2020

Sci Rep

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Breast cancer (Bc) is the leading cause of cancer-related death among women and the most commonly diagnosed cancer worldwide. Although in recent years large-scale efforts have focused on identifying new therapeutic targets, a better understanding of BC molecular processes is required. Here we focused on elucidating the molecular hallmarks of BC heterogeneity and the oncogenic mutations involved in precision medicine that remains poorly defined. To fill this gap, we established an OncoOmics strategy that consists of analyzing genomic alterations, signaling pathways, protein-protein interactome network, protein expression, dependency maps in cell lines and patient-derived xenografts in 230 previously prioritized genes to reveal essential genes in breast cancer. As results, the OncoOmics BC essential genes were rationally filtered to 140. mRNA up-regulation was the most prevalent genomic alteration. The most altered signaling pathways were associated with basal-like and Her2-enriched molecular subtypes . RAC1, AKT1, CCND1, PIK3CA, ERBB2, CDH1, MAPK14, TP53, MAPK1, SRC, RAC3, BCL2, CTNNB1, EGFR, CDK2, GRB2, MED1 and GATA3 were essential genes in at least three oncoomics approaches. Drugs with the highest amount of clinical trials in phases 3 and 4 were paclitaxel, docetaxel, trastuzumab, tamoxifen and doxorubicin. Lastly, we collected ~3,500 somatic and germline oncogenic variants associated with 50 essential genes, which in turn had therapeutic connectivity with 73 drugs. In conclusion, the OncoOmics strategy reveals essential genes capable of accelerating the development of targeted therapies for precision oncology.Breast cancer (BC) is a complex and heterogeneous disease characterized by an intricate interplay between different biological aspects such as ethnicity, genomic alterations, gene expression deregulation, hormone disruption, signaling pathway alterations, hypoxia, and environmental determinants 1,2 . Over the last years, prevention, treatment and survival strategies have evolved favorably; however, there are BC profiles that remain incurable 3 .

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“…The Hippo pathway plays important roles in immune response, stem cell function and tumor suppression. However, alterations in this pathway are involved in the BC tumorigenesis and metastasis 79 . Lastly, the thyroid hormone signaling pathway is an important regulator of growth and metabolism.…”

Section: Discussionmentioning

confidence: 99%

OncoOmics approaches to reveal essential genes in breast cancer: a panoramic view from pathogenesis to precision medicine

López‐Cortés

Paz‐y‐Miño

Guerrero

et al. 2019

Preprint

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SUMMARYBreast cancer (BC) is a heterogeneous disease where each OncoOmics approach needs to be fully understood as a part of a complex network. Therefore, the main objective of this study was to analyze genetic alterations, signaling pathways, protein-protein interaction networks, protein expression, dependency maps and enrichment maps in 230 previously prioritized genes by the Consensus Strategy, the Pan-Cancer Atlas, the Pharmacogenomics Knowledgebase and the Cancer Genome Interpreter, in order to reveal essential genes to accelerate the development of precision medicine in BC. The OncoOmics essential genes were rationally filtered to 144, 48 (33%) of which were hallmarks of cancer and 20 (14%) were significant in at least three OncoOmics approaches: RAC1, AKT1 CCND1, PIK3CA, ERBB2, CDH1, MAPK14, TP53, MAPK1, SRC, RAC3, PLCG1, GRB2, MED1, TOP2A, GATA3, BCL2, CTNNB1, EGFR and CDK2. According to the Open Targets Platform, there are 111 drugs that are currently being analyzed in 3151 clinical trials in 39 genes. Lastly, there are more than 800 clinical annotations associated with 94 genes in BC pharmacogenomics.

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Targeting the Hippo Pathway for Breast Cancer Therapy

Cited by 89 publications

References 139 publications

The Tumor Suppressor CYLD Inhibits Mammary Epithelial to Mesenchymal Transition by the Coordinated Inhibition of YAP/TAZ and TGFβ Signaling

The Tumor Suppressor CYLD Inhibits Mammary Epithelial to Mesenchymal Transition by the Coordinated Inhibition of YAP/TAZ and TGFβ Signaling

OncoOmics approaches to reveal essential genes in breast cancer: a panoramic view from pathogenesis to precision medicine

OncoOmics approaches to reveal essential genes in breast cancer: a panoramic view from pathogenesis to precision medicine

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