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PMID: 19597504 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

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

Nature medicine ·Vol. 15 ·No. 8 ·2009-08-00 ·Pages 960-6

Korpal M, Yan J, Lu X, Xu S, Lerit DA, Kang Y

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.

MeSH Terms
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
Chemicals
Smad4 Protein Smad4 protein, mouse Transforming Growth Factor beta
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Korpal Manav
Department of Molecular Biology, Princeton University, Princeton, New Jersey, USA.
Yan Jun
Lu Xin
Xu Shuwa
Lerit Dorothy A
Kang Yibin
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Article Info
Journal
Nature medicine
Abbr.
Nat Med
ISSN
1546-170X
DOI
10.1038/nm.1943
Published
2009-08-00
Epub
2009-00-13
Pages
960-6
Language
English
Region
United States
NLM ID
9502015
Subset
IM
Corrections
CommentIn
-
External Links
PubMed source DOI: 10.1038/nm.1943 View journal details
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