title: 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.
authors: BRIGHT Institute, Washington University, St Louis, Missouri 63110, USA.
authors: Kun
authors: K
authors: Zhang
authors: Callie A
authors: CA
authors: Corsa
authors: Suzanne M
authors: SM
authors: Ponik
authors: Julie L
authors: JL
authors: Prior
authors: David
authors: D
authors: Piwnica-Worms
authors: Kevin W
authors: KW
authors: Eliceiri
authors: Patricia J
authors: PJ
authors: Keely
authors: Gregory D
authors: GD
authors: Longmore
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D015820:Cadherins / Q000096:biosynthesis; D018270:Carcinoma, Ductal, Breast / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D000070818:Discoidin Domain Receptors; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D010766:Phosphorylation; D034622:RNA Interference; D034741:RNA, Small Interfering; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D038981:Receptors, Collagen / Q000378:metabolism; D011975:Receptors, Mitogen / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D015820:Cadherins; D034741:RNA, Small Interfering; D038981:Receptors, Collagen; D011975:Receptors, Mitogen; C000604407:SNAI1 protein, human; C000604429:Snai1 protein, mouse; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D000070818:Discoidin Domain Receptors; D020794:Receptor Protein-Tyrosine Kinases; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1
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