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

  • Korpal M
  • Yan J
  • Lu X
 et al. 
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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 metastasis-associated signaling pathways and will expedite the development and characterization of therapeutic agents.

Author-supplied keywords

  • Animals
  • Biological
  • Bone Neoplasms
  • Bone Neoplasms: diagnosis
  • Bone Neoplasms: metabolism
  • Bone Neoplasms: secondary
  • Bone Neoplasms: therapy
  • Breast Neoplasms
  • Breast Neoplasms: diagnosis
  • Breast Neoplasms: metabolism
  • Breast Neoplasms: pathology
  • Breast Neoplasms: therapy
  • Cultured
  • Diagnostic Imaging
  • Diagnostic Imaging: methods
  • Female
  • Genetic Vectors
  • Humans
  • Mice
  • Models
  • Nude
  • Signal Transduction
  • Signal Transduction: drug effects
  • Smad4 Protein
  • Smad4 Protein: genetics
  • Smad4 Protein: metabolism
  • Transforming Growth Factor beta
  • Transforming Growth Factor beta: pharmacokinetics
  • Treatment Outcome
  • Tumor Cells
  • Validation Studies as Topic
  • Xenograft Model Antitumor Assays

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  • Manav Korpal

  • Jun Yan

  • Xin Lu

  • Shuwa Xu

  • Dorothy A Lerit

  • Yibin Kang

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