Dataset Information

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.

SUBMITTER: Saldana SM

PROVIDER: S-EPMC3764163 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Inhibition of type I insulin-like growth factor receptor signaling attenuates the development of breast cancer brain metastasis.

Saldana Sandra M SM Lee Heng-Huan HH Lowery Frank J FJ Khotskaya Yekaterina B YB Xia Weiya W Zhang Chenyu C Chang Shih-Shin SS Chou Chao-Kai CK Steeg Patricia S PS Yu Dihua D Hung Mien-Chie MC

PloS one 20130905 9

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 pho ...[more]

PMID: 24039934

Similar Datasets

Project description:Platelet-derived growth factor receptor-beta (PDGFRβ) is a receptor tyrosine kinase found in cells of mesenchymal origin such as fibroblasts and pericytes. Activation of this receptor is dependent on paracrine ligand induction, and its preferred ligand PDGFB is released by neighboring epithelial and endothelial cells. While expression of both PDGFRβ and PDGFB has been noted in patient breast tumors for decades, how PDGFB-to-PDGFRβ tumor-stroma signaling mediates breast cancer initiation, progression, and metastasis remains unclear. Here we demonstrate this paracrine signaling pathway that mediates both primary tumor growth and metastasis, specifically, metastasis to the brain. Elevated levels of PDGFB accelerated orthotopic tumor growth and intracranial growth of mammary tumor cells, while mesenchymal-specific expression of an activating mutant PDGFRβ (PDGFRβD849V) exerted proproliferative signals on adjacent mammary tumor cells. Stromal expression of PDGFRβD849V also promoted brain metastases of mammary tumor cells expressing high PDGFB when injected intravenously. In the brain, expression of PDGFRβD849V was observed within a subset of astrocytes, and aged mice expressing PDGFRβD849V exhibited reactive gliosis. Importantly, the PDGFR-specific inhibitor crenolanib significantly reduced intracranial growth of mammary tumor cells. In a tissue microarray comprised of 363 primary human breast tumors, high PDGFB protein expression was prognostic for brain metastases, but not metastases to other sites. Our results advocate the use of mice expressing PDGFRβD849V in their stromal cells as a preclinical model of breast cancer-associated brain metastases and support continued investigation into the clinical prognostic and therapeutic use of PDGFB-to-PDGFRβ signaling in women with breast cancer. SIGNIFICANCE: These studies reveal a previously unknown role for PDGFB-to-PDGFRβ paracrine signaling in the promotion of breast cancer brain metastases and support the prognostic and therapeutic clinical utility of this pathway for patients.See related article by Wyss and colleagues, p. 594.

Project description:The development and progression of the great majority of breast cancers (BCs) are mainly dependent on the biological action elicited by estrogens through the classical estrogen receptor (ER), as well as the alternate receptor named G-protein-coupled estrogen receptor (GPER). In addition to estrogens, other hormones and growth factors, including the insulin and insulin-like growth factor system (IIGFs), play a role in BC. IIGFs cooperates with estrogen signaling to generate a multilevel cross-communication that ultimately facilitates the transition toward aggressive and life-threatening BC phenotypes. In this regard, the majority of BC deaths are correlated with the formation of metastatic lesions at distant sites. A thorough scrutiny of the biological and biochemical events orchestrating metastasis formation and dissemination has shown that virtually all cell types within the tumor microenvironment work closely with BC cells to seed cancerous units at distant sites. By establishing an intricate scheme of paracrine interactions that lead to the expression of genes involved in metastasis initiation, progression, and virulence, the cross-talk between BC cells and the surrounding microenvironmental components does dictate tumor fate and patients' prognosis. Following (i) a description of the main microenvironmental events prompting BC metastases and (ii) a concise overview of estrogen and the IIGFs signaling and their major regulatory functions in BC, here we provide a comprehensive analysis of the most recent findings on the role of these transduction pathways toward metastatic dissemination. In particular, we focused our attention on the main microenvironmental targets of the estrogen-IIGFs interplay, and we recapitulated relevant molecular nodes that orientate shared biological responses fostering the metastatic program. On the basis of available studies, we propose that a functional cross-talk between estrogens and IIGFs, by affecting the BC microenvironment, may contribute to the metastatic process and may be regarded as a novel target for combination therapies aimed at preventing the metastatic evolution.

Project description:Pathological cardiac hypertrophy is commonly associated with an upregulation of fetal genes, fibrosis, cardiac dysfunction, and heart failure. Previous studies have demonstrated that gastrodin (GAS) exerts cardioprotective action in the treatment of cardiac hypertrophy. However, the mechanism by which GAS protects against cardiac hypertrophy is yet to be elucidated. A mouse model of myocardial hypertrophy was established using an angiotensin II (Ang II) induction. GAS (5 or 50 mg/kg/d) was orally administered every day starting 7 days prior to the Ang II infusion combined with sham-operated controls. Heart samples from each group were collected for RNA sequencing. Using bioinformatics analysis, the key differentially expressed genes (DEGs) that are involved in reversing cardiac function were identified. Through bioinformatics analysis, the key DEGs that are involved in GAS's inhibition of Ang II-induced abnormal gene expression within the heart were identified. This was further validated using quantitative real-time PCR and Western blotting in neonatal rat cardiomyocytes (NRCMs). Oral administration of GAS significantly suppressed the Ang II-induced increase in heart size and heart weight to body weight. Furthermore, pretreatment of the NRCMs with GAS led to a dose-dependent inhibition of Ang II-induced increases in Nppb mRNA expression. We identified 620 upregulated and 87 downregulated Ang II-induced DEGs II, among which the expression patterns of 58 and 146 genes were inverted by low-dose and high-dose GAS, respectively. These inverted DEGs were found to be mainly enriched in the biological processes of regulation of Ras protein signal transduction, heart contraction, covalent chromatin modification, glucose metabolism, and positive regulation of cell cycle. Among them, the insulin-like growth factor type 2 (Igf2) gene, which was found to be highly reversed and downregulated by GAS, served as a core gene linking energy metabolism, immune regulation, and systemic development. Subsequent functional verification demonstrated that IGF2, and its receptor IGF2R, is one of the targets of GAS that helps protect against cardiac hypertrophy. Taken together, we have identified, for the first time, IGF2/IGF2R as a potential target influenced by GAS in the prevention of cardiac hypertrophy.

Dataset Information

Inhibition of type I insulin-like growth factor receptor signaling attenuates the development of breast cancer brain metastasis.

Publications

Inhibition of type I insulin-like growth factor receptor signaling attenuates the development of breast cancer brain metastasis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets