title: N-cadherin/FGFR promotes metastasis through epithelial-to-mesenchymal transition and stem/progenitor cell-like properties.
abstract: N-cadherin and HER2/neu were found to be co-expressed in invasive breast carcinomas. To test the contribution of N-cadherin and HER2 in mammary tumor metastasis, we targeted N-cadherin expression in the mammary epithelium of the MMTV-Neu mouse. In the context of ErbB2/Neu, N-cadherin stimulated carcinoma cell invasion, proliferation and metastasis. N-cadherin caused fibroblast growth factor receptor (FGFR) upmodulation, resulting in epithelial-to-mesenchymal transition (EMT) and stem/progenitor like properties, involving Snail and Slug upregulation, mammosphere formation and aldehyde dehydrogenase activity. N-cadherin potentiation of the FGFR stimulated extracellular signal regulated kinase (ERK) and protein kinase B (AKT) phosphorylation resulting in differential effects on metastasis. Although ERK inhibition suppressed cyclin D1 expression, cell proliferation and stem/progenitor cell properties, it did not affect invasion or EMT. Conversely, AKT inhibition suppressed invasion through Akt 2 attenuation, and EMT through Snail inhibition, but had no effect on cyclin D1 expression, cell proliferation or mammosphere formation. These findings suggest N-cadherin/FGFR has a pivotal role in promoting metastasis through differential regulation of ERK and AKT, and underscore the potential for targeting the FGFR in advanced ErbB2-amplified breast tumors.
authors: Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA.
authors: X
authors: X
authors: Qian
authors: Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA.
authors: A
authors: A
authors: Anzovino
authors: Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA.
authors: S
authors: S
authors: Kim
authors: Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA.
authors: K
authors: K
authors: Suyama
authors: Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA.
authors: J
authors: J
authors: Yao
authors: Manchester Breast Centre and Breakthrough Breast Cancer Research Unit, Paterson Institute for Cancer Research, University of Manchester, Manchester, UK.
authors: J
authors: J
authors: Hulit
authors: Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA.
authors: G
authors: G
authors: Agiostratidou
authors: Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA.
authors: N
authors: N
authors: Chandiramani
authors: Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA.
authors: H M
authors: HM
authors: McDaid
authors: Department of Pathology, Mount Sinai School of Medicine, New York, NY, USA.
authors: C
authors: C
authors: Nagi
authors: Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA.
authors: H W
authors: HW
authors: Cohen
authors: Department of Neuroscience, Mount Sinai School of Medicine, New York, NY, USA.
authors: G R
authors: GR
authors: Phillips
authors: Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors: L
authors: L
authors: Norton
authors: Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA.
authors: R B
authors: RB
authors: Hazan
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000096:biosynthesis; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D001943:Breast Neoplasms / Q000473:pathology*; D015820:Cadherins / Q000096:biosynthesis / Q000235:genetics*; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000096:biosynthesis; D004159:Diphenylamine / Q000031:analogs & derivatives / Q000494:pharmacology; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000556:secondary; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors; D051379:Mice; D008822:Mice, Transgenic; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D000071250:Snail Family Transcription Factors; D018874:Spheroids, Cellular / Q000473:pathology; D013234:Stem Cells / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D014407:Tumor Cells, Cultured
chemical_list: D000444:Aldehyde Dehydrogenase; D001549:Benzamides; D015820:Cadherins; D019938:Cyclin D1; D004159:Diphenylamine; D048049:Extracellular Signal-Regulated MAP Kinases; D048369:MAP Kinase Kinase 1; D051057:Proto-Oncogene Proteins c-akt; D011743:Pyrimidines; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases; D017468:Receptors, Fibroblast Growth Factor; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; C530105:Ccnd1 protein, mouse; C115711:PD 173074; C000604407:SNAI1 protein, human; C000604449:Snai2 protein, mouse; C506614:mirdametinib; C508053:ERBB2 protein, human; C514862:Akt1 protein, mouse; C494922:Akt2 protein, mouse; C491753:Akt3 protein, mouse; C482127:Map2k1 protein, mouse
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