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The collagen receptor discoidin domain receptor 2 stabilizes SNAIL1 to facilitate breast cancer metastasis.

ABSTRACT: Increased stromal collagen deposition in human breast tumours correlates with metastases. We show that activation of the collagen I receptor DDR2 (discoidin domain receptor 2) regulates SNAIL1 stability by stimulating ERK2 activity, in a Src-dependent manner. Activated ERK2 directly phosphorylates SNAIL1, leading to SNAIL1 nuclear accumulation, reduced ubiquitylation and increased protein half-life. DDR2-mediated stabilization of SNAIL1 promotes breast cancer cell invasion and migration in vitro, and metastasis in vivo. DDR2 expression was observed in most human invasive ductal breast carcinomas studied, and was associated with nuclear SNAIL1 and absence of E-cadherin expression. We propose that DDR2 maintains SNAIL1 level and activity in tumour cells that have undergone epithelial-mesenchymal transition (EMT), thereby facilitating continued tumour cell invasion through collagen-I-rich extracellular matrices by sustaining the EMT phenotype. As such, DDR2 could be an RTK (receptor tyrosine kinase) target for the treatment of breast cancer metastasis.

SUBMITTER: Zhang K

PROVIDER: S-EPMC3794710 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

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The collagen receptor discoidin domain receptor 2 stabilizes SNAIL1 to facilitate breast cancer metastasis.

Zhang Kun K Corsa Callie A CA Ponik Suzanne M SM Prior Julie L JL Piwnica-Worms David D Eliceiri Kevin W KW Keely Patricia J PJ Longmore Gregory D GD

Nature cell biology 20130505 6

Increased stromal collagen deposition in human breast tumours correlates with metastases. We show that activation of the collagen I receptor DDR2 (discoidin domain receptor 2) regulates SNAIL1 stability by stimulating ERK2 activity, in a Src-dependent manner. Activated ERK2 directly phosphorylates SNAIL1, leading to SNAIL1 nuclear accumulation, reduced ubiquitylation and increased protein half-life. DDR2-mediated stabilization of SNAIL1 promotes breast cancer cell invasion and migration in vitro ...[more]

PMID: 23644467

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Project description:During tumour dissemination, invading breast carcinoma cells become confronted with a reactive stroma, a type I collagen-rich environment endowed with anti-proliferative and pro-apoptotic properties. To develop metastatic capabilities, tumour cells must acquire the capacity to cope with this novel microenvironment. How cells interact with and respond to their microenvironment during cancer dissemination remains poorly understood. To address the impact of type I collagen on the fate of tumour cells, human breast carcinoma MCF-7 cells were cultured within three-dimensional type I collagen gels (3D COL1). Using this experimental model, we have previously demonstrated that membrane type-1 matrix metalloproteinase (MT1-MMP), a proteinase overexpressed in many aggressive tumours, promotes tumour progression by circumventing the collagen-induced up-regulation of BIK, a pro-apoptotic tumour suppressor, and hence apoptosis. Here we performed a transcriptomic analysis to decipher the molecular mechanisms regulating 3D COL1-induced apoptosis in human breast cancer cells. Control and MT1-MMP expressing MCF-7 cells were cultured on two-dimensional plastic plates or within 3D COL1 and a global transcriptional time-course analysis was performed. Shifting the cells from plastic plates to 3D COL1 activated a complex reprogramming of genes implicated in various biological processes. Bioinformatic analysis revealed a 3D COL1-mediated alteration of key cellular functions including apoptosis, cell proliferation, RNA processing and cytoskeleton remodelling. By using a panel of pharmacological inhibitors, we identified discoidin domain receptor 1 (DDR1), a receptor tyrosine kinase specifically activated by collagen, as the initiator of 3D COL1-induced apoptosis. Our data support the concept that MT1-MMP contributes to the inactivation of the DDR1-BIK signalling axis through the cleavage of collagen fibres and/or the alteration of DDR1 receptor signalling unit, without triggering a drastic remodelling of the transcriptome of MCF-7 cells.

Dataset Information

The collagen receptor discoidin domain receptor 2 stabilizes SNAIL1 to facilitate breast cancer metastasis.

Publications

The collagen receptor discoidin domain receptor 2 stabilizes SNAIL1 to facilitate breast cancer metastasis.

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