Effect of N‐cadherin misexpression by the mammary epithelium in mice

Knudsen, Karen A.; Sauer, Christa; Johnson, Keith R.; Wheelock, Margaret J.

doi:10.1002/jcb.20469

Cited by 21 publications

(15 citation statements)

References 34 publications

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“…Disruption or modulation of cadherin adhesions is an important step in initiating EMT (Clay and Halloran, 2011;Gumbiner, 2005;Nieto, 2011;Thiery et al, 2009;Wheelock et al, 2008). However, changes in cadherins are not always sufficient to induce EMT, indicating additional signals are required (Derksen et al, 2006;Knudsen et al, 2005;Maeda et al, 2005;Nelson et al, 2008;Park and Gumbiner, 2010). Here, we show that localized apical Rho-ROCK signaling in NCCs drives detachment of cell contacts, initiating motility within the neuroepithelium and EMT.…”

Section: Discussionmentioning

confidence: 71%

Rho activation is apically restricted by Arhgap1 in neural crest cells and drives epithelial-to-mesenchymal transition

Clay

Halloran

2013

Development

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Epithelial-to-mesenchymal transitions (EMTs) are crucial for morphogenesis and carcinoma metastasis, yet mechanisms controlling the underlying cell behaviors are poorly understood. RhoGTPase signaling has been implicated in EMT; however, previous studies have yielded conflicting results regarding Rho function, and its role in EMT remains poorly understood. Elucidation of precise Rho functions has been challenging because Rho signaling is highly context dependent and its activity is tightly regulated spatiotemporally within the cell. To date, few studies have examined how Rho affects cell motility in intact organisms, and the pattern of Rho activity during motile cell behaviors of EMT has not been determined in any system. Here, we image endogenous active Rho during EMT in vivo, and analyze effects of Rho and Rho-kinase (ROCK) manipulation on cell motility in vivo. We show that Rho is activated in a discrete apical region of premigratory neural crest cells during EMT, and Rho-ROCK signaling is essential for apical detachment and generation of motility within the neuroepithelium, a process that has been poorly understood. Furthermore, we find that Arhgap1 restricts Rho activation to apical areas, and this restriction is necessary for detachment. Our results provide new insight into mechanisms controlling local Rho activation and how it affects dynamic cell behaviors and actomyosin contraction during key steps of EMT in an intact living organism.

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Section: Discussionmentioning

confidence: 71%

Rho activation is apically restricted by Arhgap1 in neural crest cells and drives epithelial-to-mesenchymal transition

Clay

Halloran

2013

Development

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“…Transgenic mice expressing N-cadherin under the control of the MMTV promoter (MMTV-N-cadherin mice) produce high levels of N-cadherin in the mammary gland but do not develop mammary tumors even after multiple pregnancies (data not shown; ref. 20). This suggests that N-cadherin, although upregulated in aggressive tumors, is not a tumor initiator.…”

Section: Resultsmentioning

confidence: 99%

“…Mice expressing mouse N-cadherin in the mammary epithelium were also described previously (20). Mice used for these studies were in the FVB/N background.…”

Section: Animalsmentioning

confidence: 99%

N-Cadherin Signaling Potentiates Mammary Tumor Metastasis via Enhanced Extracellular Signal-Regulated Kinase Activation

et al. 2007

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N-cadherin is up-regulated in aggressive breast carcinomas, but its mechanism of action in vivo remains unknown. Transgenic mice coexpressing N-cadherin and polyomavirus middle T antigen (PyVmT) in the mammary epithelium displayed increased pulmonary metastasis, with no differences in tumor onset or growth relative to control PyVmT mice. PyVmT-N-cadherin tumors contained higher levels of phosphorylated extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (MAPK) than PyVmT controls, and phosphorylated ERK staining was further increased in pulmonary metastases. Tumor cell isolates from PyVmT-N-cadherin mice exhibited enhanced ERK activation, motility, invasion, and matrix metalloproteinase-9 (MMP-9) expression relative to PyVmT controls. MAPK/ERK kinase 1 inhibition in PyVmT-N-cadherin cells reduced MMP-9 production and invasion but not motility. Furthermore, inactivation of fibroblast growth factor receptor in PyVmT-N-cadherin cells reduced motility, invasion, and ERK activation but had no effect on PyVmT cells. Thus, de novo expression of N-cadherin in mammary ducts enhances metastasis of breast tumors via enhanced ERK signaling. [Cancer Res 2007;67(7):3106-16]

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“…Hence, the increase of N-cadherins against Ecadherins is a hallmark of an epithelial to mesenchymal transition (EMT) both in normal development and in metastasis [320][321][322][323]. Cadherin switches are crucial for motility, invasiveness, migration and metastasis in cancer cells [324,325]. In several works a reverse correlation between invasiveness of cancer cells and E-cadherinmediated adhesion was shown [326,327].…”

Section: Adherens Complexes In the Context Of -Catenin Signalingmentioning

confidence: 99%

Wnt/beta-Catenin Signaling and Small Molecule Inhibitors

Voronkov¹,

Krauß²

2012

CPD

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Wnt/ -catenin signaling is a branch of a functional network that dates back to the first metazoans and it is involved in a broad range of biological systems including stem cells, embryonic development and adult organs. Deregulation of components involved in Wnt/ -catenin signaling has been implicated in a wide spectrum of diseases including a number of cancers and degenerative diseases. The key mediator of Wnt signaling, -catenin, serves several cellular functions. It functions in a dynamic mode at multiple cellular locations, including the plasma membrane, where -catenin contributes to the stabilization of intercellular adhesive complexes, the cytoplasm where -catenin levels are regulated and the nucleus where -catenin is involved in transcriptional regulation and chromatin interactions. Central effectors of -catenin levels are a family of cysteine-rich secreted glycoproteins, known as Wnt morphogens. Through the LRP5/6-Frizzled receptor complex, Wnts regulate the location and activity of the destruction complex and consequently intracellularcatenin levels. However, -catenin levels and their effects on transcriptional programs are also influenced by multiple other factors including hypoxia, inflammation, hepatocyte growth factor-mediated signaling, and the cell adhesion molecule E-cadherin. The broad implications of Wnt/ -catenin signaling in development, in the adult body and in disease render the pathway a prime target for pharmacological research and development. The intricate regulation of -catenin at its various locations provides alternative points for therapeutic interventions.

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Effect of N‐cadherin misexpression by the mammary epithelium in mice

Cited by 21 publications

References 34 publications

Rho activation is apically restricted by Arhgap1 in neural crest cells and drives epithelial-to-mesenchymal transition

Rho activation is apically restricted by Arhgap1 in neural crest cells and drives epithelial-to-mesenchymal transition

N-Cadherin Signaling Potentiates Mammary Tumor Metastasis via Enhanced Extracellular Signal-Regulated Kinase Activation

Wnt/beta-Catenin Signaling and Small Molecule Inhibitors

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