| Beyond its well-characterized functions in embryonic and postnatal development, the Notch pathway has attracted increasing recognition for its role in stem cell regulation and aberrant activation in cancer. While research has shown that activation of the Notch pathway leads to tumorigenesis in breast cancer, gain-of-function mutations in the Notch receptors are rarely found in solid tumors. Moreover, the mechanism underlying the pathway's contribution to metastasis remains unknown. Here we report that elevated expression of the Notch ligand Jagged1 in breast cancer is associated with aggressive metastatic ability of tumor cells and an increased incidence of bone metastasis in patients. Further clinical evaluation revealed that Jagged1 is aberrantly expressed in the basal-like subtype of breast cancer. Functional studies in mice demonstrated that Jagged1 promotes osteolytic bone metastasis of breast cancer by activating the Notch pathway in the bone stromal microenvironment. These results may shift the paradigm for Notch signaling in breast cancer, as we define a requirement for the pathway in the supporting stroma of bone metastases rather than the tumor cells.Mechanistically, Jagged1 confers a growth advantage to tumor cells by stimulating IL-6 secretion from associated osteoblasts in a Notch- and Hey1-dependent manner. Distinct from their interaction with osteoblasts, Jagged1-expressing tumor cells directly activate osteoclast differentiation, giving rise to a severe osteolytic bone phenotype. Further investigation revealed that Jagged1 is a potent downstream mediator of the bone metastasis cytokine TGFbeta that is released as a consequence of bone destruction. These findings provided a pathological context for elevated Jagged1 expression in breast cancer metastasis, since bone-derived TGFbeta is a well-established mediator of tumor-stroma interactions in bone metastasis. Importantly, gamma-secretase inhibitor treatment reverses Jagged1-mediated bone metastasis in mice by disrupting the Notch pathway in bone stromal cells. Collectively, these findings elucidate a novel stroma-dependent mechanism for Notch signaling in breast cancer and provide preclinical evidence for gamma-secretase inhibitors as therapeutic agents against bone metastasis. |
