Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

The FGF/FGFR axis as a therapeutic target in breast cancer.

ABSTRACT: Fibroblast growth factor receptor (FGFR) signaling is a vital component of both embryonic and postnatal mammary gland development, which has prompted researchers to investigate both its relevance to breast cancer and its potential as a therapeutic target. Deregulated FGFR signaling during breast cancer occurs through various mechanisms, including amplification of the receptor genes, aberrant ligand expression, receptor mutations and translocations. Recent experimental outcomes involving both animal models and human breast cancer cell lines have led to the initiation of multiple early clinical trials investigating the safety and efficacy of small molecule FGFR inhibitors. In this article we review both the most recent discoveries and the need for further investigation of the mechanisms through which FGF/FGFR signaling has emerged as an oncogenic driver.

SUBMITTER: Brady N

PROVIDER: S-EPMC4228698 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

The FGF/FGFR axis as a therapeutic target in breast cancer.

Brady Nicholas N Chuntova Polly P Bade Lindsey K LK Schwertfeger Kathryn L KL

Expert review of endocrinology & metabolism 20130701 4

Fibroblast growth factor receptor (FGFR) signaling is a vital component of both embryonic and postnatal mammary gland development, which has prompted researchers to investigate both its relevance to breast cancer and its potential as a therapeutic target. Deregulated FGFR signaling during breast cancer occurs through various mechanisms, including amplification of the receptor genes, aberrant ligand expression, receptor mutations and translocations. Recent experimental outcomes involving both ani ...[more]

PMID: 25400686

Similar Datasets

The FGF/FGFR System in Breast Cancer: Oncogenic Features and Therapeutic Perspectives.

Project description:One of the major challenges in the treatment of breast cancer is the heterogeneous nature of the disease. With multiple subtypes of breast cancer identified, there is an unmet clinical need for the development of therapies particularly for the less tractable subtypes. Several transduction mechanisms are involved in the progression of breast cancer, therefore making the assessment of the molecular landscape that characterizes each patient intricate. Over the last decade, numerous studies have focused on the development of tyrosine kinase inhibitors (TKIs) to target the main pathways dysregulated in breast cancer, however their effectiveness is often limited either by resistance to treatments or the appearance of adverse effects. In this context, the fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) system represents an emerging transduction pathway and therapeutic target to be fully investigated among the diverse anti-cancer settings in breast cancer. Here, we have recapitulated previous studies dealing with FGFR molecular aberrations, such as the gene amplification, point mutations, and chromosomal translocations that occur in breast cancer. Furthermore, alterations in the FGF/FGFR signaling across the different subtypes of breast cancer have been described. Next, we discussed the functional interplay between the FGF/FGFR axis and important components of the breast tumor microenvironment. Lastly, we pointed out the therapeutic usefulness of FGF/FGFR inhibitors, as revealed by preclinical and clinical models of breast cancer.

| S-EPMC7603197 | biostudies-literature

FGF/FGFR Signaling in Hepatocellular Carcinoma: From Carcinogenesis to Recent Therapeutic Intervention.

Project description:Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, ranking third in cancer deaths worldwide. Over the last decade, several studies have emphasized the development of tyrosine kinase inhibitors (TKIs) to target the aberrant pathways in HCC. However, the outcomes are far from satisfactory due to the increasing resistance and adverse effects. The family of fibroblast growth factor (FGF) and its receptors (FGFR) are involved in various biological processes, including embryogenesis, morphogenesis, wound repair, and cell growth. The aberrant FGF/FGFR signaling is also observed in multiple cancers, including HCC. Anti-FGF/FGFR provides delightful benefits for cancer patients, especially those with FGF signaling alteration. More and more multi-kinase inhibitors targeting FGF signaling, pan-FGFR inhibitors, and selective FGFR inhibitors are now under preclinical and clinical investigation. This review summarizes the aberrant FGF/FGFR signaling in HCC initiating, development and treatment status, and provide new insights into the treatment of HCC.

| S-EPMC8002748 | biostudies-literature

Evaluation of the NRF1-proteasome axis as a therapeutic target in breast cancer.

Project description:Proteasomes are multi-subunit complexes that specialize in protein degradation. Cancer cells exhibit a heightened dependence on proteasome activity, presumably to support their enhanced proliferation and other cancer-related characteristics. Here, a systematic analysis of TCGA breast cancer datasets revealed that proteasome subunit transcript levels are elevated in all intrinsic subtypes (luminal, HER2-enriched, and basal-like/triple-negative) when compared to normal breast tissue. Although these observations suggest a pan-breast cancer utility for proteasome inhibitors, our further experiments with breast cancer cell lines and patient-derived xenografts (PDX) pointed to triple-negative breast cancer (TNBC) as the most sensitive subtype to proteasome inhibition. Finally, using TNBC cells, we extended our studies to in vivo xenograft experiments. Our previous work has firmly established a cytoprotective role for the transcription factor NRF1 via its ability to upregulate proteasome genes in response to proteasome inhibition. In further support of this notion, we show here that NRF1 depletion significantly reduced tumor burden in an MDA-MB-231 TNBC xenograft mouse model treated with carfilzomib. Taken together, our results point to TNBC as a particularly vulnerable breast cancer subtype to proteasome inhibition and provide a proof-of-principle for targeting NRF1 as a viable means to increase the efficacy of proteasome inhibitors in TNBC tumors.

| S-EPMC10516926 | biostudies-literature

The Autocrine FGF/FGFR System in both Skin and Uveal Melanoma: FGF Trapping as a Possible Therapeutic Approach.

Project description:Fibroblast growth factors (FGFs) play non-redundant autocrine/paracrine functions in various human cancers. The Cancer Genome Atlas (TCGA) data mining indicates that high levels of FGF and/or FGF receptor (FGFR) expression are associated with reduced overall survival, chromosome 3 monosomy and BAP1 mutation in human uveal melanoma (UM), pointing to the FGF/FGFR system as a target for UM treatment. Here, we investigated the impact of different FGF trapping approaches on the tumorigenic and liver metastatic activity of liver metastasis-derived murine melanoma B16-LS9 cells that, similar to human UM, are characterized by a distinctive hepatic tropism. In vitro and in vivo experiments demonstrated that the overexpression of the natural FGF trap inhibitor long-pentraxin 3 (PTX3) inhibits the oncogenic activity of B16-LS9 cells. In addition, B16-LS9 cells showed a reduced tumor growth and liver metastatic activity when grafted in PTX3-overexpressing transgenic mice. The efficacy of the FGF trapping approach was confirmed by the capacity of the PTX3-derived pan-FGF trap small molecule NSC12 to inhibit B16-LS9 cell growth in vitro, in a zebrafish embryo orthotopic tumor model and in an experimental model of liver metastasis. Possible translational implications for these observations were provided by the capacity of NSC12 to inhibit FGF signaling and cell proliferation in human UM Mel285, Mel270, 92.1, and OMM2.3 cells. In addition, NSC12 caused caspase-3 activation and PARP cleavage followed by apoptotic cell death as well as ?-catenin degradation and inhibition of UM cell migration. Together, our findings indicate that FGF trapping may represent a novel therapeutic strategy in UM.

| S-EPMC6770058 | biostudies-literature

The PREX1/Rac signaling axis: Potential as a biomarker and therapeutic target in breast cancer.

Project description:PREX1 is a Rac guanine exchange factor that coordinates signaling inputs from G protein-coupled receptors and receptor tyrosine kinases (RTKs). PREX1 creates a positive feedback loop to drive RTK, phosphatidylinositol 3-kinase (PI3K)/AKT, and MEK/ERK signaling. High PREX1 levels predict sensitivity to PI3K inhibitors in breast cancer cells.

| S-EPMC4905322 | biostudies-other

Addiction of mesenchymal phenotypes on the FGF/FGFR axis in oral squamous cell carcinoma cells.

Project description:The epithelial-mesenchymal transition (EMT) is a crucial morphological event that occurs during epithelial tumor progression. ZEB1/2 are EMT transcription factors that are positively correlated with EMT phenotypes and breast cancer aggressiveness. ZEB1/2 regulate the alternative splicing and hence isoform switching of fibroblast growth factor receptors (FGFRs) by repressing the epithelial splicing regulatory proteins, ESRP1 and ESRP2. Here, we show that the mesenchymal-like phenotypes of oral squamous cell carcinoma (OSCC) cells are dependent on autocrine FGF-FGFR signaling. Mesenchymal-like OSCC cells express low levels of ESRP1/2 and high levels of ZEB1/2, resulting in constitutive expression of the IIIc-isoform of FGFR, FGFR(IIIc). By contrast, epithelial-like OSCC cells showed opposite expression profiles for these proteins and constitutive expression of the IIIb-isoform of FGFR2, FGFR2(IIIb). Importantly, ERK1/2 was constitutively phosphorylated through FGFR1(IIIc), which was activated by factors secreted autonomously by mesenchymal-like OSCC cells and involved in sustained high-level expression of ZEB1. Antagonizing FGFR1 with either inhibitors or siRNAs considerably repressed ZEB1 expression and restored epithelial-like traits. Therefore, autocrine FGF-FGFR(IIIc) signaling appears to be responsible for sustaining ZEB1/2 at high levels and the EMT phenotype in OSCC cells.

| S-EPMC6827898 | biostudies-literature

Inhibition of FGF-FGFR and VEGF-VEGFR signalling in cancer treatment.

Project description:The sites of targeted therapy are limited and need to be expanded. The FGF-FGFR signalling plays pivotal roles in the oncogenic process, and FGF/FGFR inhibitors are a promising method to treat FGFR-altered tumours. The VEGF-VEGFR signalling is the most crucial pathway to induce angiogenesis, and inhibiting this cascade has already got success in treating tumours. While both their efficacy and antitumour spectrum are limited, combining FGF/FGFR inhibitors with VEGF/VEGFR inhibitors are an excellent way to optimize the curative effect and expand the antitumour range because their combination can target both tumour cells and the tumour microenvironment. In addition, biomarkers need to be developed to predict the efficacy, and combination with immune checkpoint inhibitors is a promising direction in the future. The article will discuss the FGF-FGFR signalling pathway, the VEGF-VEGFR signalling pathway, the rationale of combining these two signalling pathways and recent small-molecule FGFR/VEGFR inhibitors based on clinical trials.

| S-EPMC8016646 | biostudies-literature

The CXCL8-CXCR1/2 Axis as a Therapeutic Target in Breast Cancer Stem-Like Cells.

Project description:Cancer stem-like cells (CSC) have been targeted by different strategies over the last decade. This mini review focuses on preclinical and clinical results obtained by interfering with chemokine receptors CXCR1 and CXCR2 in breast cancer. This strategy is currently being tested in a randomized, double blind phase 2 clinical trial.

| S-EPMC6373429 | biostudies-literature

FGF/FGFR signaling in health and disease.

Project description:Growing evidences suggest that the fibroblast growth factor/FGF receptor (FGF/FGFR) signaling has crucial roles in a multitude of processes during embryonic development and adult homeostasis by regulating cellular lineage commitment, differentiation, proliferation, and apoptosis of various types of cells. In this review, we provide a comprehensive overview of the current understanding of FGF signaling and its roles in organ development, injury repair, and the pathophysiology of spectrum of diseases, which is a consequence of FGF signaling dysregulation, including cancers and chronic kidney disease (CKD). In this context, the agonists and antagonists for FGF-FGFRs might have therapeutic benefits in multiple systems.

| S-EPMC7468161 | biostudies-literature

FGFR2 Mutation p.Cys342Arg Enhances Mitochondrial Metabolism-Mediated Osteogenesis via FGF/FGFR-AMPK-Erk1/2 Axis in Crouzon Syndrome.

Project description:BackgroundCrouzon syndrome ([OMIM] #123500) caused by FGFR2 mutation is an autosomal dominant syndrome with craniosynostosis, the underlying mechanism of which remains obscure.MethodsFirst, whole exome sequencing was used to screen the possible pathogenic variant in two sporadic patients with Crouzon syndrome. The investigation of primary and secondary structures as well as the conservation analysis of FGFR2 mutation (p.Cys342Arg) was performed. Then, wild-type and mutant overexpression plasmids were constructed and transfected into pre-osteoblastic murine cell line MC3T3-E1 cells. Osteogenesis and mitochondrial metabolism were analyzed by CCK8, ALP staining and ALP activity, alizarin red staining, qRT-PCR, Western blot, seahorse assays and mitochondrial staining. The siRNA targeting FGFR2 and domain negative FGFR2 were designed for verification.ResultsFirst, FGFR2 mutation (p.Cys342Arg) was detected in two sporadic Chinese Crouzon syndrome patients. FGFR2 p.Cys342Arg promoted the osteogenic differentiation of MC3T3-E1 cells through the upregulation of AMP-activated protein kinase (AMPK)-Erk1/2 signal pathway. Furthermore, FGFR2 p.Cys342Arg enhanced oxidative phosphorylation and converted mitochondrial fusion to the fission of MC3T3-E1, promoting osteogenic differentiation and craniosynostosis in Crouzon syndrome. Additionally, AMPK or Erk1/2 inhibitors delayed the cranial suture closure.ConclusionFGFR2 mutation p.Cys342Arg promotes osteogenesis by enhancing mitochondrial metabolism-mediated via FGF/FGFR-AMPK-Erk1/2 axis, which indicates the potential of therapy targeting AMPK or Erk1/2 for syndromic craniosynostosis treatment.

| S-EPMC9563077 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data