title: Inhibition of type I insulin-like growth factor receptor signaling attenuates the development of breast cancer brain metastasis.
abstract: 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.
authors.affiliation: Department of Molecular and Cellular Oncology, the University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America ; Cancer Biology Program, the University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas, United States of America.
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Saldana
authors.forename: Heng-Huan
authors.initials: HH
authors.lastname: Lee
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Lowery
authors.forename: Yekaterina B
authors.initials: YB
authors.lastname: Khotskaya
authors.forename: Weiya
authors.initials: W
authors.lastname: Xia
authors.forename: Chenyu
authors.initials: C
authors.lastname: Zhang
authors.forename: Shih-Shin
authors.initials: SS
authors.lastname: Chang
authors.forename: Chao-Kai
authors.initials: CK
authors.lastname: Chou
authors.forename: Patricia S
authors.initials: PS
authors.lastname: Steeg
authors.forename: Dihua
authors.initials: D
authors.lastname: Yu
authors.forename: Mien-Chie
authors.initials: MC
authors.lastname: Hung
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D001932:Brain Neoplasms / Q000235:genetics / Q000556:secondary*; D001940:Breast / Q000378:metabolism / Q000473:pathology*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D005260:Female; D055786:Gene Knockout Techniques; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D010766:Phosphorylation; D017526:Receptor, IGF Type 1 / Q000235:genetics* / Q000378:metabolism
chemical_list: D018972:Insulin-Like Growth Factor Binding Protein 3; D017526:Receptor, IGF Type 1
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