[HTML][HTML] Tumor-derived JAGGED1 promotes osteolytic bone metastasis of breast cancer by engaging notch signaling in bone cells

N Sethi, X Dai, CG Winter, Y Kang - Cancer cell, 2011 - cell.com
N Sethi, X Dai, CG Winter, Y Kang
Cancer cell, 2011cell.com
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 …
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.
PaperClip
cell.com