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Interaction between the estrogen receptor and fibroblast growth factor receptor pathways in non-small cell lung cancer.
- Source :
-
Oncotarget [Oncotarget] 2017 Apr 11; Vol. 8 (15), pp. 24063-24076. - Publication Year :
- 2017
-
Abstract
- The estrogen receptor (ER) promotes non-small cell lung cancer (NSCLC) proliferation. Since fibroblast growth factors (FGFs) are known regulators of stem cell markers in ER positive breast cancer, we investigated whether a link between the ER, FGFs, and stem cell markers exists in NSCLC. In lung preneoplasias and adenomas of tobacco carcinogen exposed mice, the anti-estrogen fulvestrant and/or the aromatase inhibitor anastrozole blocked FGF2 and FGF9 secretion, and reduced expression of the stem cell markers SOX2 and nanog. Mice administered β-estradiol during carcinogen exposure showed increased FGF2, FGF9, SOX2, and Nanog expression in airway preneoplasias. In normal FGFR1 copy number NSCLC cell lines, multiple FGFR receptors were expressed and secreted several FGFs. β-estradiol caused enhanced FGF2 release, which was blocked by fulvestrant. Upon co-inhibition of ER and FGFRs using fulvestrant and the pan-FGFR inhibitor AZD4547, phosphorylation of FRS2, the FGFR docking protein, was maximally reduced, and enhanced anti-proliferative effects were observed. Combined AZD4547 and fulvestrant enhanced lung tumor xenograft growth inhibition and decreased Ki67 and stem cell marker expression. To verify a link between ERβ, the predominant ER in NSCLC, and FGFR signaling in patient tumors, mRNA analysis was performed comparing high versus low ERβ expressing tumors. The top differentially expressed genes in high ERβ tumors involved FGF signaling and human embryonic stem cell pluripotency. These results suggest interaction between the ER and FGFR pathways in NSCLC promotes a stem-like state. Combined FGFR and ER inhibition may increase the efficacy of FGFR inhibitors for NSCLC patients lacking FGFR genetic alterations.
- Subjects :
- Animals
Antineoplastic Agents, Hormonal pharmacology
Benzamides pharmacology
Biomarkers
Carcinoma, Non-Small-Cell Lung pathology
Cell Line, Tumor
Cell Proliferation drug effects
Disease Models, Animal
Estradiol analogs & derivatives
Estradiol pharmacology
Estrogens metabolism
Female
Fibroblast Growth Factors biosynthesis
Fibroblast Growth Factors metabolism
Fulvestrant
Humans
Ligands
Lung Neoplasms pathology
Mice
Neoplastic Stem Cells metabolism
Piperazines pharmacology
Protein Binding
Pyrazoles pharmacology
Receptors, Estrogen antagonists & inhibitors
Receptors, Fibroblast Growth Factor antagonists & inhibitors
Xenograft Model Antitumor Assays
Carcinoma, Non-Small-Cell Lung metabolism
Lung Neoplasms metabolism
Receptors, Estrogen metabolism
Receptors, Fibroblast Growth Factor metabolism
Signal Transduction drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1949-2553
- Volume :
- 8
- Issue :
- 15
- Database :
- MEDLINE
- Journal :
- Oncotarget
- Publication Type :
- Academic Journal
- Accession number :
- 28445992
- Full Text :
- https://doi.org/10.18632/oncotarget.16030