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

SummaryDespite 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.PaperClip To listen to this audio, enable JavaScript on your browser. However, you can download and play the audio by clicking on the icon belowHelp with MP3 filesOptionsDownload audio (5387 K)

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (195 K)Download as PowerPoint slideHighlights► 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