Dataset Information

Proteolytic cleavage of amyloid precursor protein by ADAM10 mediates proliferation and migration in breast cancer.

ABSTRACT:

Background

Amyloid precursor protein (APP), best known for its association with Alzheimer disease, has recently been implicated in breast cancer progression. However, the precise mechanism involved remains unclear. Here, we investigated the role of APP proteolytic cleavage in breast cancer functions.

Methods

The presence of APP proteolytic cleavage products was examined in breast cancer cell lines. The functional roles of APP in breast cancer were studied in vitro and tumor xenograft model using siRNA. The effects of full length APP and the ?-secretase cleaved ectodomain fragment, soluble APP? (sAPP?) were further investigated for their overexpression in breast cancers. The ?-secretase involved was identified. The ?-secretase expression together with APP was examined in clinical breast cancers.

Results

We showed that APP underwent proteolytic cleavage in breast cancer cells to generate sAPP?. The sAPP? and full length protein mediated breast cancer migration and proliferation, but in different functional extent. This proteolytic cleavage was mediated by ADAM10. Downregulation of APP and ADAM10 brought about similar functional effects. Overexpression of sAPP? reversed the effects of ADAM10 downregulation. Interestingly, in patients with non-luminal breast cancers, APP and ADAM10 expression correlated with each other and their co-expression was associated with the worst outcome.

Conclusions

These results demonstrated the contributory role of APP cleavage on its oncogenic roles in breast cancer. ADAM10 was the key ?-secretase. APP and ADAM10 co-expression was associated with worse survival in non-luminal breast cancers. Targeting of APP or its processing by ADAM10 might be a promising treatment option in these cancers.

SUBMITTER: Tsang JYS

PROVIDER: S-EPMC6306343 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Publications

Proteolytic cleavage of amyloid precursor protein by ADAM10 mediates proliferation and migration in breast cancer.

Tsang Julia Y S JYS Lee Michelle A MA Chan Tsz-Hei TH Li Joshua J Ni Yun-Bi YB Shao Yan Y Chan Siu-Ki SK Cheungc Sai-Yin SY Lau Kwok-Fai KF Tse Gary M K GMK

EBioMedicine 20181120

<h4>Background</h4>Amyloid precursor protein (APP), best known for its association with Alzheimer disease, has recently been implicated in breast cancer progression. However, the precise mechanism involved remains unclear. Here, we investigated the role of APP proteolytic cleavage in breast cancer functions.<h4>Methods</h4>The presence of APP proteolytic cleavage products was examined in breast cancer cell lines. The functional roles of APP in breast cancer were studied in vitro and tumor xenogr ...[more]

PMID: 30470613

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Project description:Amyloid precursor protein (APP) was originally identified as the source of ?-amyloid peptides that accumulate in Alzheimer's disease (AD), but it also has been implicated in the control of multiple aspects of neuronal motility. APP belongs to an evolutionarily conserved family of transmembrane proteins that can interact with a variety of adapter and signaling molecules. Recently, we showed that both APP and its insect ortholog [APPL (APP-Like)] directly bind the heterotrimeric G-protein Go?, supporting the model that APP can function as an unconventional Go?-coupled receptor. We also adapted a well characterized assay of neuronal migration in the hawkmoth, Manduca sexta, to show that APPL-Go? signaling restricts ectopic growth within the developing nervous system, analogous to the role postulated for APP family proteins in controlling migration within the mammalian cortex. Using this assay, we have now identified Manduca Contactin (MsContactin) as an endogenous ligand for APPL, consistent with previous work showing that Contactins interact with APP family proteins in other systems. Using antisense-based knockdown protocols and fusion proteins targeting both proteins, we have shown that MsContactin is selectively expressed by glial cells that ensheath the migratory neurons (expressing APPL), and that MsContactin-APPL interactions normally prevent inappropriate migration and outgrowth. These results provide new evidence that Contactins can function as authentic ligands for APP family proteins that regulate APP-dependent responses in the developing nervous system. They also support the model that misregulated Contactin-APP interactions might provoke aberrant activation of Go? and its effectors, thereby contributing to the neurodegenerative sequelae that typify AD.Members of the amyloid precursor protein (APP) family participate in many aspects of neuronal development, but the ligands that normally activate APP signaling have remained controversial. This research provides new evidence that members of the Contactin family function as authentic ligands for APP and its orthologs, and that this evolutionarily conserved class of membrane-attached proteins regulates key aspects of APP-dependent migration and outgrowth in the embryonic nervous system. By defining the normal role of Contactin-APP signaling during development, these studies also provide the framework for investigating how the misregulation of Contactin-APP interactions might contribute to neuronal dysfunction in the context of both normal aging and neurodegenerative conditions, including Alzheimer's disease.

Dataset Information

Proteolytic cleavage of amyloid precursor protein by ADAM10 mediates proliferation and migration in breast cancer.

Background

Methods

Results

Conclusions

Publications

Proteolytic cleavage of amyloid precursor protein by ADAM10 mediates proliferation and migration in breast cancer.

Similar Datasets

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