TY - JOUR
T1 - Tumor-Derived Jagged1 Promotes Osteolytic Bone Metastasis of Breast Cancer by Engaging Notch Signaling in Bone Cells
AU - Sethi, Nilay
AU - Dai, Xudong
AU - Winter, Christopher G.
AU - Kang, Yibin
N1 - Funding Information:
This work is dedicated to the memory of our colleague G.R. Mundy, whose work inspired us to venture into the field of bone metastasis research. We thank M. Korpal, Y. Wei, X. Lu, M. Blanco, E. Mu, K. Golden, L. Cong, P. Bisher, C. DeCoste, S. Ganesan, M. Tetruashvily, D. Quek, Y. Min, H. Zheng, and other members of the laboratory for technical assistance and discussions, F. Miller for the 4T1 series cell lines, M. Zhang for TM40D-MB cell line, and C.-Y. Wang for the PGA-986-1 Notch reporter plasmid. This work was funded by grants from the Brewster Foundation, Department of Defense (BC051647), New Jersey Commission on Cancer Research (NJCCR), National Institutes of Health (R01CA134519), American Cancer Society, and Merck. N.S. is a recipient of a NJCCR predoctoral fellowship, and Y.K. is an investigator of the Champalimaud Metastasis Program at Princeton University. X.D. and C.G.W. are employees and shareholders of Merck & Co., Inc.
PY - 2011/2/15
Y1 - 2011/2/15
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/79751472667
UR - https://www.scopus.com/pages/publications/79751472667#tab=citedBy
U2 - 10.1016/j.ccr.2010.12.022
DO - 10.1016/j.ccr.2010.12.022
M3 - Article
C2 - 21295524
AN - SCOPUS:79751472667
SN - 1535-6108
VL - 19
SP - 192
EP - 205
JO - Cancer Cell
JF - Cancer Cell
IS - 2
ER -