title: Tumor-derived JAGGED1 promotes osteolytic bone metastasis of breast cancer by engaging notch signaling in bone cells.
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.
authors.affiliation: Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA.
authors.forename: Nilay
authors.initials: N
authors.lastname: Sethi
authors.forename: Xudong
authors.initials: X
authors.lastname: Dai
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Winter
authors.forename: Yibin
authors.initials: Y
authors.lastname: Kang
mesh_terms: D016475:3T3 Cells; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D000818:Animals; D001859:Bone Neoplasms / Q000556:secondary*; D002135:Calcium-Binding Proteins / Q000502:physiology*; D002454:Cell Differentiation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology*; D015850:Interleukin-6 / Q000378:metabolism; D000072100:Jagged-1 Protein; D008024:Ligands; D008325:Mammary Neoplasms, Experimental / Q000473:pathology*; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D010006:Osteoblasts / Q000378:metabolism* / Q000473:pathology; D051880:Receptors, Notch / Q000378:metabolism*; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D002135:Calcium-Binding Proteins; D004791:Enzyme Inhibitors; D036341:Intercellular Signaling Peptides and Proteins; D015850:Interleukin-6; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; D008024:Ligands; D008565:Membrane Proteins; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D053829:Amyloid Precursor Protein Secretases