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Tumor-Derived Jagged1 Promotes Osteolytic Bone Metastasis of Breast Cancer by Engaging Notch Signaling in Bone Cells

Nilay N Sethi, Xudong X Dai, Christopher G CG Winter, and Yibin Y Kang

Cancer Cell 19(2):14 (2011) PMID 21295524 PMCID PMC3040415

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 TGF@b that is released during bone destruction. Importantly, @c-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 @c-secretase inhibitors for the treatment of bone metastasis. PaperClip:

Copyright © 2011 Elsevier Ltd. All rights reserved.

DOI: 10.1016/j.ccr.2010.12.022
Version: za2963e q8za0 q8zb4 q8zcc q8zdb q8zef q8zf9 q8zga
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