Fibroblast growth factor receptors in breast cancer

Wang, Shuwei; Ding, Zhongyang

doi:10.1177/1010428317698370

Cited by 33 publications

(31 citation statements)

References 67 publications

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“…Consistent with our observation, Roidl et al showed that FGFR4 gene expression is up-regulated in doxorubicin-treated, apoptosis resistant cancer cell clones [37]. Activating FGFR4 can inhibit the MAPK, PI3K/Akt or NF-κB signaling pathway depending on the cellular context [21, 24]. In this study, we observed drastic changes of Erk1/2 phosphorylation in ADR-R cells.…”

Section: Discussionsupporting

confidence: 79%

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FGFR4 Links Glucose Metabolism and Chemotherapy Resistance in Breast Cancer

Xu¹,

Chen²,

Yang³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Poor response to chemotherapy leads to the relapse and metastatic progression of tumors. Reprogrammed glucose metabolism is one of the important hallmarks of cancer that facilitates cancer cell survival, proliferation and chemoresistance. However, the precise fate of glucose metabolism and its role in therapy responsiveness in cancers remains largely unexplored. Methods: The glycolytic phenotype of doxorubicin (ADR)-resistant breast cancer cells and their parental cells was assessed by measuring glucose uptake, lactate release, and extracellular acidification rate (ECAR). Protein expression was detected by Western blotting analysis and mRNA expression was detected using q-PCR. Cell survival ratio was determined by the cell counting kit 8 assay. The role of fibroblast growth factor receptor 4 (FGFR4) in glycolysis, chemoresistance, and the underlying mechanisms were studied by using gene expression microarray and short hairpin RNA-mediated gene knockdown. Results: We found that glycolytic flux are increased in two doxorubicin (ADR)-resistant breast cancer cell lines compared with their parental wild type cells, as demonstrated by increased glucose uptake, lactate release, and extracellular acidification rate (ECAR). By gene expression microarray, we identified FGFR4 as a critical modulator of ADR resistance and enhanced glucose metabolism. Genetic silencing of FGFR4 increased the chemosensitivity and suppressed the enhanced glycolytic flux in ADR-resistant cells. Mechanistically, activation of FGFR4 signaling in ADR-resistant cells led to the phosphorylation of FGF receptor substrate 2 (FRS2) and further activated the downstream MAPK/ERK signaling. Pharmacological inhibition of FGFR4-FRS2-ERK signaling pathway significantly blocked the chemoresistant and glycolytic phenotypes of ADR-resistant cells. Conclusion: Our findings suggest that high levels of FGFR4 can increase glucose metabolism and lead to chemoresistance in breast cancer and reveal the mechanistic basis for targeting FGFR4 as a therapeutic opportunity for chemoresistant tumors.

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Section: Discussionsupporting

confidence: 79%

“…The binding of FGFR4s to the corresponding FGF ligands causes receptor dimerization and transphosphorylation of FGFR tyrosine domains [21-23]. Activated FGFR phosphorylates FGF receptor substrate 2 (FRS2) and leads to the activation of downstream signaling pathways, including MAPK, PI3K/AKT, and NF-κB [15, 18, 24].…”

Section: Resultsmentioning

confidence: 99%

FGFR4 Links Glucose Metabolism and Chemotherapy Resistance in Breast Cancer

Xu¹,

Chen²,

Yang³

et al. 2018

Cell Physiol Biochem

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“…Additionally, recent reports suggest that FGFR3 may participate in a molecular pathway leading to breast cancer development. This fact indicates that the FGFR3 protein might be a target to be considered in FGFR3-related breast cancer 63 . FIGF is related with tumor cell migration in colorectal cancer metastasis 64 .…”

Section: Discussionmentioning

confidence: 96%

“…IGF-I promotes tumor cell proliferation, malignant transformation, development of new vessels and tumor development 62 . FGFR3 high levels directly correlate with poor prognosis in mammary tumors 63 . Additionally, recent reports suggest that FGFR3 may participate in a molecular pathway leading to breast cancer development.…”

Section: Discussionmentioning

confidence: 99%

Usefulness of melatonin as complementary to chemotherapeutic agents at different stages of the angiogenic process

González-González

González

Rueda

et al. 2020

Sci Rep

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chemotherapeutics are sometimes administered with drugs, like antiangiogenic compounds, to increase their effectiveness. Melatonin exerts antitumoral actions through antiangiogenic actions. We studied if melatonin regulates the response of HUVECs to chemotherapeutics (docetaxel and vinorelbine). The inhibition that these agents exert on some of the processes involved in angiogenesis, such as, cell proliferation, migratory capacity or vessel formation, was enhanced by melatonin. Regarding to estrogen biosynthesis, melatonin impeded the negative effect of vinorelbine, by decreasing the activity and expression of aromatase and sulfatase. Docetaxel and vinorelbine increased the expression of VEGF-A, VEGF-B, VEGF-C, VEGFR-1, VEGFR-3, ANG1 and/or ANG-2 and melatonin inhibited these actions. Besides, melatonin prevented the positive actions that docetaxel exerts on the expression of other factors related to angiogenesis like JAG1, ANPEP, IGF-1, CXCL6, AKT1, ERK1, ERK2, MMP14 and NOS3 and neutralized the stimulating actions of vinorelbine on the expression of FIGF, FGFR3, CXCL6, CCL2, ERK1, ERK2, AKT1, NOS3 and MMP14. In CAM assay melatonin inhibited new vascularization in combination with chemotherapeutics. Melatonin further enhanced the chemotherapeutics-induced inhibition of p-AKt and p-eRK and neutralized the chemotherapeuticscaused stimulatory effect on HUVECs permeability by modifying the distribution of VE cadherin. Our results confirm that melatonin blocks proangiogenic and potentiates antiangiogenic effects induced by docetaxel and vinorelbine enhancing their antitumor effectiveness.The development of new blood vessels is needed to provide oxygen and nutrients to the tumor cells and a way to escape from the primary site 1 . Angiogenesis is a main step in tumor growth and antiangiogenic agents are considered an interesting complementary strategy in cancer therapy 2 . Angiogenesis is a multi-step process: endothelial cell activation by growth factors, degradation of capillary wall by proteinases, formation of a branch point in the vessel wall, migration of endothelial cells and proliferation and reorganisation of endothelial cells to form tubules. In tumors, the interaction between endothelial cells and the microenvironment stimulates endothelial cells to proliferate, migrate and form a branching network of tubes 3 . A balance between angiogenic activating and inhibiting factors regulates the evolution of endothelial cells from a quiescent to a proangiogenic stage 2 . Among the principal proangiogenic factors are vascular endothelial growth factor (VEGF) and angiopoietins (ANG) 4,5 . Angiogenesis depends on the coordinated balance in time between the production of VEGF and angiopoietins 6 .Melatonin, produced in the pineal gland, has antitumor effects in different cancer types, especially hormone-dependent tumors 7-10 . Melatonin oncostatic actions are exerted through different mechanisms, such as: indirect effects through a down-regulation of gonadal estrogens 11 ; direct antiestrogenic actions at the tumor cell ...

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“…FGF ligand binding to the FGFR caused receptor dimerization, transphosphorylation and activation of an intracellular tyrosine kinase domain (25). FGFR1 binds to the ligand FGF to activate the PI3K-AKT, IP3-PLC/DAG, JAK-STAT (26) and other signaling pathways which regulate cell self-renewal, metabolism, proliferation, EMT and angiogenesis (27,28). Recent studies revealed that the FGFR family, especially FGFR1, was abnormally highly expressed in a variety of tumor tissues like prostate, pancreatic and cervical cancer, as well as gliomas (29) (Fig.…”

Section: Discussionmentioning

confidence: 99%

Cross-link regulation of precursor N-cadherin and FGFR1 by GDNF increases U251MG cell viability

Tang

Liu

et al. 2018

Oncol Rep

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Glial cell line-derived neurotrophic factor (GDNF) is considered to be involved in the development of glioma. However, uncovering the underlying mechanism of the proliferation of glioma cells is a challenging work in progress. We have identified the binding of the precursor of N-cadherin (proN-cadherin) and GDNF on the cell membrane in previous studies. In the present study, we observed increased U251 Malignant glioma (U251MG) cell viability by exogenous GDNF (50 ng/ml). We also confirmed that the high expression of the proN-cadherin was stimulated by exogenous GDNF. Concurrently, we affirmed that lower expression of proN-cadherin correlated with reduced glioma cell viability. Additionally, we observed glioma cell U251MG viability as the phosphorylation level of FGFR1 at Y653 and Y654 was increased after exogenous GDNF treatment, which led to increased interaction between proN-cadherin and FGFR1 (pY653+Y654). Our experiments presented a new mechanism adopted by GDNF supporting glioma development and indicated a possible therapeutic potential via the inhibition of proN-cadherin/FGFR1 interaction.

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Fibroblast growth factor receptors in breast cancer

Cited by 33 publications

References 67 publications

FGFR4 Links Glucose Metabolism and Chemotherapy Resistance in Breast Cancer

FGFR4 Links Glucose Metabolism and Chemotherapy Resistance in Breast Cancer

Usefulness of melatonin as complementary to chemotherapeutic agents at different stages of the angiogenic process

Cross-link regulation of precursor N-cadherin and FGFR1 by GDNF increases U251MG cell viability

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