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Nat Med. 2009 Aug;15(8):960-6. doi: 10.1038/nm.1943. Epub 2009 Jul 13.

Imaging transforming growth factor-beta signaling dynamics and therapeutic response in breast cancer bone metastasis.

Author information

1
Department of Molecular Biology, Princeton University, Princeton, New Jersey, USA.

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.

Comment in

  • Immunotherapy. 2009 Nov;1(6):925-7.
PMID:
19597504
DOI:
10.1038/nm.1943
[Indexed for MEDLINE]

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