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.
Highlights
Brain metastases are the most frequent type of malignant brain tumors, and they commonly originate from lung, breast, melanoma, renal, and colon cancers [1,2,3]
Previous studies suggest that IGF-1 signaling and IGF-IR activation play a role in the brain specificity of metastatic breast cancer [19,21]
We first immunoprecipitated the IGF-IR β subunit with a specific antibody that does not cross-react with the insulin receptor, followed by immunoblotting with phospho-IGFIR antibody against Tyr 1131, the earliest autophosphorylation site that is absolutely required for IGF-1 ligand-dependent IGFIR function [15]
Summary
Brain metastases are the most frequent type of malignant brain tumors, and they commonly originate from lung, breast, melanoma, renal, and colon cancers [1,2,3]. IGF-IR becomes autophosphorylated at Tyr 1131, 1135, and 1136 in the β subunit and subsequently recruits a host of proteins, including IRS-2, that activate signaling via PI3K/AKT and Ras/Raf/MAPK pathways to promote cell motility and pro-metastatic behavior in breast cancer cells [10,15,16]. The insulin-like growth factor binding protein-3 (IGFBP3) is the major binding protein and regulator of IGF-1 ligand bioavailability and has been reported to inhibit as well as potentiate the activity of IGF-IR signaling in different cancers [22,23,24]. IGFBP3 was shown to stimulate IGF-IR phosphorylation indirectly through activation of sphingosine kinase 1 (SphK1) and EGFR transactivation [24] Adding yet another layer of complexity is the finding that IGFBP3 expression itself can be regulated by IGF-1 ligand through. Using an experimental brain metastasis model, we found that ablation of IGF-IR expression can prevent the outgrowth of brain metastases, suggesting that this signaling pathway merits further study as a potential target for the treatment of breast cancer brain metastasis
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