A Mouse Model for in Vivo Detection and Disruption of TGF-Beta Signaling in Breast Cancer Metastasis
Annual summary rept. 1 Sep 2008-31 Aug 2009
PRINCETON UNIV NJ
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Although the transforming growth factor-beta TGF-beta pathway has been implicated in breast cancer metastasis, its in vivo dynamics and temporal-spatial involvement in organ-specific metastasis have not been investigated. Here we engineered a xenograft model system with a conditional control of the TGF-beta-SMAD signaling pathway and a dual-luciferase reporter system for tracing both metastatic burden and TGF-beta signaling activity in vivo. Strong TGF-beta signaling in osteolytic bone lesions is suppressed directly by genetic and pharmacological disruption of the TGF-beta-SMAD pathway and indirectly by inhibition of osteoclast function with bisphosphonates. Notably, disruption of TGF-beta signaling early in metastasis can substantially reduce metastasis burden but becomes less effective when bone lesions are well established. Our in vivo system for real-time manipulation and detection of TGF-beta signaling provides a proof of principle for using similar strategies to analyze the in vivo dynamics of other metastasisassociated signaling pathways and will expedite the development and characterization of therapeutic agents.
- Medicine and Medical Research