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Open AccessArticle

GPER Mediates a Feedforward FGF2/FGFR1 Paracrine Activation Coupling CAFs to Cancer Cells toward Breast Tumor Progression

Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy
University of Natural Resources and Life Sciences, 1180 Vienna, Austria
Regional Hospital, 87100 Cosenza, Italy
Endocrinology, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi-Nesima Hospital, 95122 Catania, Italy
Author to whom correspondence should be addressed.
Cells 2019, 8(3), 223;
Received: 18 February 2019 / Revised: 1 March 2019 / Accepted: 4 March 2019 / Published: 7 March 2019
(This article belongs to the Special Issue Fibroblast Growth Factor Receptor (FGFR) Signaling Pathway in Tumor)
The FGF2/FGFR1 paracrine loop is involved in the cross-talk between breast cancer cells and components of the tumor stroma as cancer-associated fibroblasts (CAFs). By quantitative PCR (qPCR), western blot, immunofluorescence analysis, ELISA and ChIP assays, we demonstrated that 17β-estradiol (E2) and the G protein estrogen receptor (GPER) agonist G-1 induce the up-regulation and secretion of FGF2 via GPER together with the EGFR/ERK/c-fos/AP-1 signaling cascade in (ER)-negative primary CAFs. Evaluating the genetic alterations from METABRIC and TCGA datasets, we then assessed that FGFR1 is the most frequently amplified FGFRs family member and its amplification/expression associates with shorter survival rates in breast cancer patients. Therefore, in order to assess the functional FGF2/FGFR1 interplay between CAFs and breast cancer cells, we generated the FGFR1-knockout MDA-MB-231 cells using CRISPR/Cas9 genome editing strategy. Using conditioned medium from estrogen-stimulated CAFs, we established that the activation of FGF2/FGFR1 paracrine signaling triggers the expression of the connective tissue growth factor (CTGF), leading to the migration and invasion of MDA-MB-231 cells. Our findings shed new light on the role elicited by estrogens through GPER in the activation of the FGF2/FGFR1 signaling. Moreover, our findings may identify further biological targets that could be considered in innovative combination strategies halting breast cancer progression. View Full-Text
Keywords: cancer-associated fibroblasts; GPER; breast cancer; estrogen; FGFR1; FGF2 cancer-associated fibroblasts; GPER; breast cancer; estrogen; FGFR1; FGF2
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Santolla, M.F.; Vivacqua, A.; Lappano, R.; Rigiracciolo, D.C.; Cirillo, F.; Galli, G.R.; Talia, M.; Brunetti, G.; Miglietta, A.M.; Belfiore, A.; Maggiolini, M. GPER Mediates a Feedforward FGF2/FGFR1 Paracrine Activation Coupling CAFs to Cancer Cells toward Breast Tumor Progression. Cells 2019, 8, 223.

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