Imaging transforming growth factor-beta signaling dynamics and therapeutic response in breast cancer bone metastasis.
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.
Korpal
Manav
M
Department of Molecular Biology, Princeton University, Princeton, New Jersey, USA.
Yan
Jun
J
Lu
Xin
X
Xu
Shuwa
S
Lerit
Dorothy A
DA
Kang
Yibin
Y
D000818:Animals; D001859:Bone Neoplasms / Q000175:diagnosis* / Q000378:metabolism / Q000556:secondary* / Q000628:therapy; D001943:Breast Neoplasms / Q000175:diagnosis / Q000378:metabolism / Q000473:pathology* / Q000628:therapy; D003952:Diagnostic Imaging / Q000379:methods*; D005260:Female; D005822:Genetic Vectors; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008954:Models, Biological; D015398:Signal Transduction / Q000187:drug effects; D051901:Smad4 Protein / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000493:pharmacokinetics*; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured; D054928:Validation Studies as Topic; D023041:Xenograft Model Antitumor Assays
D051901:Smad4 Protein; C490810:Smad4 protein, mouse; D016212:Transforming Growth Factor beta