Abstract |
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 metastasis-associated signaling pathways and will expedite the development and characterization of therapeutic agents.
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Authors | Manav Korpal, Jun Yan, Xin Lu, Shuwa Xu, Dorothy A Lerit, Yibin Kang |
Journal | Nature medicine
(Nat Med)
Vol. 15
Issue 8
Pg. 960-6
(Aug 2009)
ISSN: 1546-170X [Electronic] United States |
PMID | 19597504
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
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Chemical References |
- Smad4 Protein
- Smad4 protein, mouse
- Transforming Growth Factor beta
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Topics |
- Animals
- Bone Neoplasms
(diagnosis, metabolism, secondary, therapy)
- Breast Neoplasms
(diagnosis, metabolism, pathology, therapy)
- Diagnostic Imaging
(methods)
- Female
- Genetic Vectors
- Humans
- Mice
- Mice, Nude
- Models, Biological
- Signal Transduction
(drug effects)
- Smad4 Protein
(genetics, metabolism)
- Transforming Growth Factor beta
(pharmacokinetics)
- Treatment Outcome
- Tumor Cells, Cultured
- Validation Studies as Topic
- Xenograft Model Antitumor Assays
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