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Tumor-derived Jagged1 associated with breast cancer bone metastases
Sethi N. Cancer Cell. 2011;doi:10.1016/j.ccr.2010.12.022.
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The Notch ligand Jagged1 appears to be an important mediator of bone metastasis by activating the Notch pathway in bone cells in patients with breast cancer.
Researchers assessed the endogenous expression of pathway ligands, receptors and downstream targets in the 4T1 series of mouse mammary tumor cell lines.
To determine whether Jagged1 was functionally important for the development of bone metastasis in breast cancer, researchers used a short-hairpin RNA to silence Jagged1 expression in sterol carrier protein-2 (SCP2) and 1833 sublines. Mice were then injected with tumor cells. Progression of bone metastases was monitored using bioluminescence imaging.
Researchers found that JAG1 knockdown extended survival and delayed the onset of bone metastases in test mice. Although there were no differences in early time points, bioluminescence imaging showed that JAG1 knockdown reduced bone tumor burden by six- to 10-fold 3 weeks after injection.
Researchers said the results suggested that tumor-derived Jagged1 is necessary for efficient outgrowth of bone lesions.
Sethi and colleagues then over-expressed Jagged1 in the mildly metastatic MDA-231 subline SCP28 to learn whether enforced expression would promote bone metastasis. Mice injected with JAG1 over-expressing tumor cells had developed bone metastases earlier, displayed a significant increase in bone metastasis burden and developed severe osteolytic bone lesions.
Further, Ki67 staining of bone metastases showed a greater number of proliferating cancer cells in the JAG1 over-expressing group.
“Importantly, we found that Notch pathway target genes were elevated in the tumor-associated stroma of JAG1 over-expressing bone metastases using mouse-specific [reverse transcriptase-polymerase chain reaction] analysis,” the researchers wrote. “These findings indicate that enforced expression of Jagged1 is sufficient to promote osteolytic bone metastasis, potentially by activating the Notch pathway in the supporting bone microenvironment.”
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