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

• Published in: Nature medicine Vol. 15; no. 8; pp. 960 - 966
• Main Authors: Korpal, Manav, Yan, Jun, Lu, Xin, Xu, Shuwa, Lerit, Dorothy A, Kang, Yibin
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.08.2009; Nature Publishing Group
• Subjects: Animals; Biomedical and Life Sciences; Biomedicine; Bone cancer; Bone Neoplasms - diagnosis; Bone Neoplasms - metabolism; Bone Neoplasms - secondary; Bone Neoplasms - therapy; Breast cancer; Breast Neoplasms - diagnosis; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Breast Neoplasms - therapy; Cancer Research; Control; Development and progression; Diagnostic Imaging - methods; Diphosphonates; Female; Genetic aspects; Genetic Vectors; Health aspects; Humans; Infectious Diseases; Metabolic Diseases; Metastasis; Mice; Mice, Nude; Models, Biological; Molecular Medicine; Neurosciences; Risk factors; Signal Transduction - drug effects; Smad4 Protein - genetics; Smad4 Protein - metabolism; technical-report; Transforming Growth Factor beta - pharmacokinetics; Transforming growth factors; Treatment Outcome; Tumor Cells, Cultured; Validation Studies as Topic; Xenograft Model Antitumor Assays; United States
• ISSN: 1078-8956; 1546-170X; 1546-170X
• DOI: 10.1038/nm.1943

Although the TGF-β signaling pathway has been implicated in breast cancer metastasis, studies are hampered by a lack of animal models for in vivo analysis of metastasis signaling pathways. Here a noninvasive xenograft model is described that uses a dual bioluminescence reporter system to study TGF-β signaling in bone metastasis. Disruption of TGF-β signaling in early—not late—stage metastasis is shown to markedly reduce bone metastasis burden. Although the transforming growth factor-β (TGF-β) 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-β–SMAD signaling pathway and a dual-luciferase reporter system for tracing both metastatic burden and TGF-β signaling activity in vivo . Strong TGF-β signaling in osteolytic bone lesions is suppressed directly by genetic and pharmacological disruption of the TGF-β–SMAD pathway and indirectly by inhibition of osteoclast function with bisphosphonates. Notably, disruption of TGF-β 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-β 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.