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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Aldehyde Dehydrogenase / biosynthesis
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Animals
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Benzamides / pharmacology
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Breast Neoplasms / pathology*
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Cadherins / biosynthesis
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Cadherins / genetics*
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Cell Movement / genetics
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Cell Proliferation
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Cyclin D1 / biosynthesis
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Diphenylamine / analogs & derivatives
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Diphenylamine / pharmacology
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Epithelial-Mesenchymal Transition* / genetics
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Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
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Extracellular Signal-Regulated MAP Kinases / biosynthesis*
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Female
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Humans
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Lung Neoplasms / secondary
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MAP Kinase Kinase 1 / antagonists & inhibitors
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Mice
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Mice, Transgenic
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Neoplasm Invasiveness
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Neoplasm Metastasis
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Phosphorylation
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / metabolism*
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Pyrimidines / pharmacology
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RNA Interference
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RNA, Small Interfering
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Receptor, ErbB-2 / antagonists & inhibitors
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Receptor, ErbB-2 / biosynthesis
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Receptor, ErbB-2 / genetics
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Receptors, Fibroblast Growth Factor / antagonists & inhibitors
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Receptors, Fibroblast Growth Factor / biosynthesis
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Receptors, Fibroblast Growth Factor / genetics*
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Signal Transduction / genetics
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Snail Family Transcription Factors
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Spheroids, Cellular / pathology
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Stem Cells / metabolism
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Transcription Factors / antagonists & inhibitors
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Transcription Factors / biosynthesis
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Tumor Cells, Cultured
Substances
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Benzamides
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Cadherins
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Ccnd1 protein, mouse
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PD 173074
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Pyrimidines
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RNA, Small Interfering
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Receptors, Fibroblast Growth Factor
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SNAI1 protein, human
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Snai2 protein, mouse
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Snail Family Transcription Factors
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Transcription Factors
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Cyclin D1
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mirdametinib
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Diphenylamine
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Aldehyde Dehydrogenase
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ERBB2 protein, human
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Receptor, ErbB-2
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Akt1 protein, mouse
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Akt2 protein, mouse
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Akt3 protein, mouse
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Proto-Oncogene Proteins c-akt
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Extracellular Signal-Regulated MAP Kinases
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MAP Kinase Kinase 1
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Map2k1 protein, mouse