Journal
PLOS ONE
Volume 8, Issue 9, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0073406
Keywords
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Categories
Funding
- U.S. Department of Defense (DOD) Breast Cancer Research Program, Center of Excellence (COE) [W81 XWH-062-0033]
- National Institutes of Health [CA109311, CA099031, CCSG CA16672]
- Susan G. Komen for the Cure
- University of Texas MD Anderson-China Medical University
- Hospital Sister Institution Fund
- Cancer Research Center of Excellence (Taiwan) [DOH102-TD-C-111-005]
- Program for Stem Cell and Regenerative Medicine Frontier Research (Taiwan) [NSC101-2321-B-039-001]
- International Research-Intensive Centers of Excellence in Taiwan (Taiwan) [NSC102-2911-I-002-303]
- Center for Biological Pathways
- Patel Memorial Breast Cancer Endowment Fund
- GSBS
- DOD CDMR-BCRP [W81XWH-10-1-0749]
- DOD [W81XWH-10-BCRP-POSTDOC]
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Brain metastasis is a common cause of mortality in cancer patients, yet potential therapeutic targets remain largely unknown. The type I insulin-like growth factor receptor (IGF-IR) is known to play a role in the progression of breast cancer and is currently being investigated in the clinical setting for various types of cancer. The present study demonstrates that IGF-IR is constitutively autophosphorylated in brain-seeking breast cancer sublines. Knockdown of IGF-IR results in a decrease of phospho-AKT and phospho-p70s6k, as well as decreased migration and invasion of MDA-MB-231Br brain-seeking cells. In addition, transient ablation of IGFBP3, which is overexpressed in brain-seeking cells, blocks IGF-IR activation. Using an in vivo experimental brain metastasis model, we show that IGF-IR knockdown brain-seeking cells have reduced potential to establish brain metastases. Finally, we demonstrate that the malignancy of brain-seeking cells is attenuated by pharmacological inhibition with picropodophyllin, an IGF-IR-specific tyrosine kinase inhibitor. Together, our data suggest that the IGF-IR is an important mediator of brain metastasis and its ablation delays the onset of brain metastases in our model system.
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