Loss of E-Cadherin-Dependent Cell–Cell Adhesion and the Development and Progression of Cancer

Bruner, Heather C; Derksen, Patrick W.B.

doi:10.1101/cshperspect.a029330

Cited by 167 publications

(126 citation statements)

References 169 publications

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“…41 Loss of cell-cell adhesion associated with CDH1 abnormalities contributes to both the development and progression of cancers. 42 FOXA2 is a positive regulator of CDH1 expression and altered FOXA2 activity has been linked to epithelial-to-mesenchymal transition (EMT) in breast and pancreatic cancer. 33, 34 It is important to note, however, that it remains uncertain if loss of CDH1 drives EMT or if dysregulation of CDH1 is a result of EMT.…”

Section: Discussionmentioning

confidence: 99%

Functional characterization of recurrent FOXA2 mutations seen in endometrial cancers

Neff

Rush

Smith

et al. 2018

Intl Journal of Cancer

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FOXA2, a member of the forkhead family of DNA-binding proteins, is frequently mutated in uterine cancers. Most of the mutations observed in uterine cancers are frameshifts and stops. FOXA2 is considered to be a driver gene in uterine cancers, functioning as a haploinsufficient tumor suppressor. The functional consequences of FOXA2 mutations, however, have not yet been determined. We evaluated the effects that frameshift mutations and a recurrent missense mutation have on FOXA2 transcriptional activity. Recurrent N-terminal frameshifts resulted in truncated proteins that failed to translocate to the nucleus and have no transcriptional activity using an E-cadherin/luciferase reporter assay. Protein abundance was reduced for the recurrent p.S169 W mutation, as was transcriptional activity. A C-terminal frameshift mutation had increased FOXA2 levels evidenced by both Western blot and immunofluorescence. Given that FOXA2 is a recognized activator of E-cadherin (CDH1) expression and E-cadherin's potential role in epithelial-to-mesenchymal transition in a wide range of cancer types, we tested the hypothesis that FOXA2 mutations in primary uterine cancer specimens would be associated with reduced CDH1 transcript levels. qRT-PCR revealed significantly lower levels of CDH1 expression in primary tumors with FOXA2 mutations. Our findings in vitro and in vivo suggest that reduced transcriptional activity associated with FOXA2 mutations in uterine cancers is likely to contribute to protumorigenic changes in gene expression.

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Section: Discussionmentioning

confidence: 99%

Functional characterization of recurrent FOXA2 mutations seen in endometrial cancers

Neff

Rush

Smith

et al. 2018

Intl Journal of Cancer

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“…In tumors, it functions as a powerful molecular barrier that inhibits cancer cell proliferation, shedding, invasion, and metastasis . The absence of functional E‐cadherin possibly caused by truncating mutations, loss of heterozygosity, and transcriptional repression is causal for invasive lobular breast carcinoma, which is a subtype of breast cancer . In addition, it has shown that E‐cadherin improves IGF1R recruitment to adherens junctions, possibly resulting in receptor sequestration and signaling repression.…”

Section: Discussionmentioning

confidence: 99%

“…21 The absence of functional E-cadherin possibly caused by truncating mutations, loss of heterozygosity, and transcriptional repression is causal for invasive lobular breast carcinoma, which is a subtype of breast cancer. 22 In addition, it has…”

Section: Discussionmentioning

confidence: 99%

Glutamate Ionotropic Receptor Kainate Type Subunit 3 (GRIK3) promotes epithelial‐mesenchymal transition in breast cancer cells by regulating SPDEF/CDH1 signaling

Xiao

Kuang

Zhang

et al. 2019

Molecular Carcinogenesis

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Glutamate Ionotropic Receptor Kainate Type Subunit 3 (GRIK3) is an important excitatory neurotransmitter receptor that plays a significant role in various neurodegenerative diseases. However, the biological functions of GRIK3 in malignancies are largely unknown because of limited related studies. Here, we primarily reported that the expression of GRIK3 was higher in breast cancer tissues than in adjacent noncancerous tissues. GRIK3 expression was also positively correlated with the prognosis of patients with breast cancer. GRIK3 promoted the proliferation and migration abilities of breast cancer cells and enhanced the growth of orthotopically implanted tumors. Mechanically, GRIK3 influenced a range of signaling pathways and key signal transducers, including two epithelial‐mesenchymal transition regulators, SPDEF and CDH1. Heterogenous expression of SPDEF and CDH1 counteracted the migration and invasion abilities, respectively, of breast cancer cells induced by GRIK3. Moreover, overexpression of GRIK3 increased the expression of mesenchymal markers and decreased the expression of epithelial markers, resulting in the translocation of β‐catenin into the nucleus and the increased β‐catenin transcriptional activity. In conclusion, the present study reported a novel oncogenic role of GRIK3. Meanwhile, GRIK3, as a membrane receptor, may also serve as a potential therapeutic target for the treatment of breast cancer.

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“…To our knowledge, prior studies that used E-cadherin-coated surfaces have not reported on the formation of E-cadherin adhesions corresponding to this crucial range of elasticity. E-cadherin is a well-known tumor suppressor but is continued to be expressed in many types of cancers [19]. It has been shown that modulation of E-cadherin adhesion may play a key role in cancer progression [20].…”

Section: Introductionmentioning

confidence: 99%

Epithelial Cell-like Elasticity Modulates E-cadherin Adhesion Organization

Eftekharjoo

Chatterji

Maruthamuthu

2020

Preprint

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E-cadherin adhesions are essential for cell-to-cell cohesion and mechanical coupling between epithelial cells and reside in a micro-environment that comprises the adjoining epithelial cells. While E-cadherin has been shown to be a mechanosensor, it is unknown if E-cadherin adhesions can differentially sense stiffness within the range of that of epithelial cells. A survey of literature shows that epithelial cells' Young's moduli of elasticity lie predominantly in the sub kPa to few kPa range, with cancer cells often being softer than non-cancerous ones. Here, we devised oriented E-cadherin-coated soft silicone substrates with sub kPa or few kPa elasticity, but with similar viscous moduli, and found that E-cadherin adhesions differentially organize depending on the magnitude of epithelial cell-like elasticity. Linearly shaped E-cadherin adhesions associated with radially oriented actin, but not irregularly shaped E-cadherin adhesions associated with circumferential actin foci, were much more numerous on 2.4 kPa E-cadherin substrates compared to 0.3 kPa E-cadherin substrates. However, the total amount of E-cadherin in both types of adhesions taken together was similar on the 0.3 kPa and 2.4 kPa E-cadherin substrates, across many cells. Furthermore, while the average extent of nuclear recruitment of the mechanoresponsive transcription factor YAP on the 0.3 kPa E-cadherin substrate was undiminished relative to that on the 2.4 kPa substrate, a fraction of cells on the softer substrate displayed relatively high levels of YAP nuclear recruitment. Our results show that E-cadherin adhesions can be regulated by epithelial cell-like elasticity and have significant implications for disease states like carcinomas characterized by altered epithelial cell elasticity.

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Loss of E-Cadherin-Dependent Cell–Cell Adhesion and the Development and Progression of Cancer

Cited by 167 publications

References 169 publications

Functional characterization of recurrent FOXA2 mutations seen in endometrial cancers

Functional characterization of recurrent FOXA2 mutations seen in endometrial cancers

Glutamate Ionotropic Receptor Kainate Type Subunit 3 (GRIK3) promotes epithelial‐mesenchymal transition in breast cancer cells by regulating SPDEF/CDH1 signaling

Epithelial Cell-like Elasticity Modulates E-cadherin Adhesion Organization

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