Journal
CELLS
Volume 8, Issue 3, Pages -Publisher
MDPI
DOI: 10.3390/cells8030223
Keywords
cancer-associated fibroblasts; GPER; breast cancer; estrogen; FGFR1; FGF2
Categories
Funding
- Italian Association for Cancer Research (AIRC) [IG 21322]
- Fondazione Umberto Veronesi (Post-Doctoral Fellowship 2019)
- [AIRC-IG 19242]
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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 17 beta-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.
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