Imaging Transforming Growth Factor-beta Signaling Dynamics and Therapeutic Response in Breast Cancer Bone Metastasis

Overview

Journal Nat Med

Specialties General Medicine
Molecular Biology

Date 2009 Jul 15

PMID 19597504

Citations 115

Authors

Manav Korpal

Jun Yan

Xin Lu

Shuwa Xu

Dorothy A Lerit

Yibin Kang

Affiliations

Soon will be listed here.

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.

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