Cancer Cell
Volume 19, Issue 2, 15 February 2011, Pages 192-205
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Article
Tumor-Derived Jagged1 Promotes Osteolytic Bone Metastasis of Breast Cancer by Engaging Notch Signaling in Bone Cells

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Summary

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.

Highlights

► Jagged1 promotes osteolytic bone metastasis by activating stromal Notch signaling ► Notch signaling induces IL-6 secretion from osteoblasts to stimulate tumor growth ► Jagged1 is an essential functional target of TGFβ in osteolytic bone metastasis ► GSI inhibits Jagged1-mediated bone metastasis by targeting stromal Notch signaling

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Present address: Sage Bionetworks, Seattle, WA 98109, USA