Linked Life Data

20460524

Source:http://linkedlifedata.com/resource/pubmed/id/20460524

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
10
pubmed:dateCreated
2010-5-14
pubmed:abstractText
Members of the fibroblast growth factor receptor (FGFR) family have essential roles in normal physiology and in cancer where they control diverse processes. FGFRs have been associated with breast cancer development. Thus, models to study the role of FGFR in breast cancer and their targeting potential are important. We present an in vitro and in vivo analysis of FGFRs in the breast cancer model cell lines 67NR and 4T1. We show that both tumor cell lines coexpress FGFRs and ligands and display autocrine FGFR signaling activity. Fibroblast growth factor receptor substrate 2 (FRS2), a downstream mediator of FGFR, is constitutively tyrosine phosphorylated and multiple signaling pathways are active. Treatment of 67NR and 4T1 cultures with TKI258, an FGFR tyrosine kinase inhibitor (TKI), caused a rapid decrease in FRS2 phosphorylation; decreased the activity of extracellular signal-regulated kinase 1/2 (ERK1/2), AKT, and phospholipase Cgamma; and blocked proliferation of both tumor lines. Furthermore, TKI258 induced 4T1 apoptotic cell death via blockade of the phosphoinositide 3-kinase/AKT pathway. In vivo, one dose of TKI258 rapidly lowered FRS2 phosphorylation and ERK1/2 and AKT activity in mammary tumors. Long-term TKI258 treatment of 4T1 tumor- and 67NR tumor-bearing mice had a significant effect on primary tumor outgrowth and 4T1 tumor-induced lung metastases. A microarray analysis was carried out to identify targets with roles in TKI258 antitumor activity and potential prognostic markers in human breast tumors. Of interest are the downregulated matrix metalloproteases (MMP), in particular MMP9, which is essential for metastatic spread of 4T1 tumors.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
May
pubmed:issn
1538-7445
pubmed:author
pubmed:copyrightInfo
(c)2010 AACR.
pubmed:issnType
Electronic
pubmed:day
15
pubmed:volume
70
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
4151-62
pubmed:dateRevised
2010-11-18
pubmed:meshHeading
pubmed-meshheading:20460524-Animals, pubmed-meshheading:20460524-Apoptosis, pubmed-meshheading:20460524-Blotting, Western, pubmed-meshheading:20460524-Cell Movement, pubmed-meshheading:20460524-Cell Proliferation, pubmed-meshheading:20460524-Enzyme-Linked Immunosorbent Assay, pubmed-meshheading:20460524-Female, pubmed-meshheading:20460524-Gene Expression Profiling, pubmed-meshheading:20460524-Humans, pubmed-meshheading:20460524-Lung Neoplasms, pubmed-meshheading:20460524-Mammary Neoplasms, Experimental, pubmed-meshheading:20460524-Mice, pubmed-meshheading:20460524-Mice, Inbred BALB C, pubmed-meshheading:20460524-Mitogen-Activated Protein Kinase 1, pubmed-meshheading:20460524-Mitogen-Activated Protein Kinase 3, pubmed-meshheading:20460524-Oligonucleotide Array Sequence Analysis, pubmed-meshheading:20460524-Phosphatidylinositol 3-Kinases, pubmed-meshheading:20460524-Phospholipase C gamma, pubmed-meshheading:20460524-Phosphorylation, pubmed-meshheading:20460524-Protein Kinase Inhibitors, pubmed-meshheading:20460524-Proto-Oncogene Proteins c-akt, pubmed-meshheading:20460524-Receptors, Fibroblast Growth Factor, pubmed-meshheading:20460524-Signal Transduction, pubmed-meshheading:20460524-Tumor Cells, Cultured, pubmed-meshheading:20460524-Tumor Markers, Biological, pubmed-meshheading:20460524-Tyrosine
pubmed:year
2010
pubmed:articleTitle
Targeting fibroblast growth factor receptors blocks PI3K/AKT signaling, induces apoptosis, and impairs mammary tumor outgrowth and metastasis.
pubmed:affiliation
Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't