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

1
Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy
2
University of Natural Resources and Life Sciences, 1180 Vienna, Austria
3
Regional Hospital, 87100 Cosenza, Italy
4
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; https://doi.org/10.3390/cells8030223
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)
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Abstract

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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