Abstract
Despite evidence supporting an oncogenic role in breast cancer, the Notch pathway's contribution to metastasis remains unknown. Here, we report that the Notch ligand Jagged1 is a clinically and functionally important mediator of bone metastasis by activating the Notch pathway in bone cells. Jagged1 promotes tumor growth by stimulating IL-6 release from osteoblasts and directly activates osteoclast differentiation. Furthermore, Jagged1 is a potent downstream mediator of the bone metastasis cytokine TGFβ that is released during bone destruction. Importantly, γ-secretase inhibitor treatment reduces Jagged1-mediated bone metastasis by disrupting the Notch pathway in stromal bone cells. These findings elucidate a stroma-dependent mechanism for Notch signaling in breast cancer and provide rationale for using γ-secretase inhibitors for the treatment of bone metastasis.
Copyright © 2011 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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3T3 Cells
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Amyloid Precursor Protein Secretases / antagonists & inhibitors
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Animals
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Bone Neoplasms / secondary*
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Calcium-Binding Proteins / physiology*
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Cell Differentiation
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Enzyme Inhibitors / pharmacology
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Intercellular Signaling Peptides and Proteins / physiology*
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Interleukin-6 / metabolism
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Jagged-1 Protein
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Ligands
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Mammary Neoplasms, Experimental / pathology*
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Membrane Proteins / physiology*
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Mice
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Osteoblasts / metabolism*
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Osteoblasts / pathology
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Receptors, Notch / metabolism*
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Serrate-Jagged Proteins
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Signal Transduction*
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Smad Proteins / metabolism
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Transforming Growth Factor beta / metabolism
Substances
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Calcium-Binding Proteins
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Enzyme Inhibitors
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Intercellular Signaling Peptides and Proteins
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Interleukin-6
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Jag1 protein, mouse
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Jagged-1 Protein
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Ligands
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Membrane Proteins
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Receptors, Notch
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Serrate-Jagged Proteins
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Smad Proteins
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Transforming Growth Factor beta
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Amyloid Precursor Protein Secretases