Nephronectin is Correlated with Poor Prognosis in Breast Cancer and Promotes Metastasis via its Integrin-Binding Motifs

Steigedal, Tonje S.; Toraskar, Jimita Prashant; Redvers, Richard P.; Valla, Marit; Magnussen, Synnøve; Bofin, Anna M.; Opdahl, Signe; Lundgren, Steinar; Eckhardt, Bedrich L.; Lamar, John M.; Doherty, Judy P.; Hynes, Richard O.; Anderson, Robin L.; Svineng, Gunbjørg

doi:10.1016/j.neo.2018.02.008

Cited by 26 publications

(59 citation statements)

References 53 publications

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“…Metastasis is responsible for poor outcome of BC. 22 The clinical association study has found that overexpression of Ezrin was significantly associated with BC metastasis. To investigate the effects of Ezrin on the metastatic ability of BC cells, we performed wound-healing and Transwell assays.…”

Section: Ezrin Promotes Bc Metastasis Via Emt In Vitro and In Vivomentioning

confidence: 99%

Ezrin promotes breast cancer progression by modulating AKT signals

Kong

Lin

et al. 2019

Br J Cancer

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BACKGROUND: Ezrin, which is known as a cytoskeleton linker protein, is closely linked with the metastatic progression of cancer and is frequently abnormally expressed in aggressive cancer types. However, the possible involvement of Ezrin in metastasis and angiogenesis in breast cancer remains unclear. METHODS: Immunohistochemical analysis of Ezrin was performed on both BC samples (n = 117) and normal epithelium samples (n = 47). In vivo and in vitro assays were performed to validate the effect of Ezrin on AKT pathway-mediated BC progression. RESULTS: In this study, Ezrin was found to be upregulated in BC tissues, which was linked with aggressive tumour characteristics and poor prognosis. Moreover, we showed that Ezrin promotes BC proliferation, migration, invasion, and angiogenesis in vitro and in vivo. Mechanistic analysis showed that Ezrin interacted with AKT, and promoted its kinase activity, thereby regulating the AKT pathway in BC. CONCLUSIONS: In all, we propose a model for an Ezrin/AKT oncoprotein axis, which provides novel insight into how Ezrin contributes to BC progression.

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Section: Ezrin Promotes Bc Metastasis Via Emt In Vitro and In Vivomentioning

confidence: 99%

Ezrin promotes breast cancer progression by modulating AKT signals

Kong

Lin

et al. 2019

Br J Cancer

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“…Knock down of NPNT in highly metastatic cells caused a significant reduction in metastasis to the lungs, liver and spine 18 . More recently, we demonstrated that NPNT promotes lung metastasis in mice through its integrinbinding motifs 19 . A comprehensive study of NPNT protein expression patterns in human primary BC revealed NPNT as a potential prognostic marker for BC 19 .…”

Section: Introductionmentioning

confidence: 96%

Nephronectin promotes breast cancer brain metastatic colonization via its integrin-binding domains

Magnussen

Toraskar

Wilhelm

et al. 2020

Sci Rep

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this study demonstrates a role for the extracellular matrix protein nephronectin (npnt) in promoting experimental breast cancer brain metastasis, possibly through enhanced binding to-and migration through brain endothelial cells. With the introduction of more targeted breast cancer treatments, a prolonged survival has resulted during the last decade. Consequently, an increased number of patients develop metastasis in the brain, a challenging organ to treat. We recently reported that NPNT was highly expressed in primary breast cancer and associated with unfavourable prognosis. The current study addresses our hypothesis that npnt promotes brain metastases through its integrin-binding motifs. SAGE-sequencing revealed that NPNT was significantly up-regulated in human breast cancer tissue compared to pair-matched normal breast tissue. Human brain metastatic breast cancers expressed both NPNT and its receptor, integrin α8β1. Using an open access repository; BreastMark, we found a correlation between high NPNT mRNA levels and poor prognosis for patients with the luminal B subtype. The 66cl4 mouse cell line was used for expression of wild-type and mutant NPNT, which is unable to bind α8β1. Using an in vivo model of brain metastatic colonization, 66cl4-NPNT cells showed an increased ability to form metastatic lesions compared to cells with mutant NPNT, possibly through reduced endothelial adhesion and transmigration. Abbreviations AMPK AMP-activated protein kinase BC Breast cancer EGF Epidermal growth factor EGFR Epidermal growth factor receptor EIE Glutamic acid-isoleucine-glutamic acid ER Estrogen receptor EV Empty vector FFPE Formalin fixed paraffin embedded HER2 Human epidermal growth factor receptor 2 IHC Immunohistochemistry MBEC Mouse brain endothelial cells NPNT Nephronectin

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“…This indicates that p38 MAPK functions downstream of NPNT and regulates viability of the 66cl4 cells. These observations were further validated by comparing the parental 66cl4 cells, with low endogenous NPNT, to the parental 4T1 cells, with high endogenous NPNT levels [12,14]. The 66cl4 cell line generally showed lower p38 MAPK phosphorylation compared to the 4T1 cells ( Fig.…”

Section: Npnt Mediates Cell Viability Via P38 Signaling Pathwaysmentioning

confidence: 85%

Nephronectin mediates p38 MAPK‐induced cell viability via its integrin‐binding enhancer motif

et al. 2018

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Nephronectin ( NPNT ) is an extracellular matrix ( ECM ) protein involved in kidney development. We recently reported intracellular NPNT as a potential prognostic marker in breast cancer and that NPNT promotes metastasis in an integrin‐dependent manner. Here, we used reverse‐phase protein array ( RPPA ) to analyze NPNT ‐triggered intracellular signaling in the 66cl4 mouse breast cancer cell line. The results showed that the integrin‐binding enhancer motif is important for the cellular effects upon NPNT interaction with its receptors, including phosphorylation of p38 mitogen‐activated protein kinase ( MAPK ). Furthermore, analysis using prediction tools suggests involvement of NPNT in promoting cell viability. In conclusion, our results indicate that NPNT , via its integrin‐binding motifs, promotes cell viability through phosphorylation of p38 MAPK .

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Nephronectin is Correlated with Poor Prognosis in Breast Cancer and Promotes Metastasis via its Integrin-Binding Motifs

Cited by 26 publications

References 53 publications

Ezrin promotes breast cancer progression by modulating AKT signals

Ezrin promotes breast cancer progression by modulating AKT signals

Nephronectin promotes breast cancer brain metastatic colonization via its integrin-binding domains

Nephronectin mediates p38 MAPK‐induced cell viability via its integrin‐binding enhancer motif

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