GPER Mediates a Feedforward FGF2/FGFR1 Paracrine Activation Coupling CAFs to Cancer Cells Toward Breast Tumor Progression
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-estradio...
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MDPI AG
2019-03-01
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| Online Access: | http://www.mdpi.com/2073-4409/8/3/223 |
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| author | Maria Francesca Santolla Adele Vivacqua Rosamaria Lappano Damiano Cosimo Rigiracciolo Francesca Cirillo Giulia Raffaella Galli Marianna Talia Giuseppe Brunetti Anna Maria Miglietta Antonino Belfiore Marcello Maggiolini |
| author_facet | Maria Francesca Santolla Adele Vivacqua Rosamaria Lappano Damiano Cosimo Rigiracciolo Francesca Cirillo Giulia Raffaella Galli Marianna Talia Giuseppe Brunetti Anna Maria Miglietta Antonino Belfiore Marcello Maggiolini |
| author_sort | Maria Francesca Santolla |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-12T07:52:52Z |
| format | Article |
| id | doaj.art-697682672ad549d381eb71b4b41132d3 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-12T07:52:52Z |
| publishDate | 2019-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-697682672ad549d381eb71b4b41132d32023-09-02T20:27:52ZengMDPI AGCells2073-44092019-03-018322310.3390/cells8030223cells8030223GPER Mediates a Feedforward FGF2/FGFR1 Paracrine Activation Coupling CAFs to Cancer Cells Toward Breast Tumor ProgressionMaria Francesca Santolla0Adele Vivacqua1Rosamaria Lappano2Damiano Cosimo Rigiracciolo3Francesca Cirillo4Giulia Raffaella Galli5Marianna Talia6Giuseppe Brunetti7Anna Maria Miglietta8Antonino Belfiore9Marcello Maggiolini10Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, ItalyDepartment of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, ItalyDepartment of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, ItalyDepartment of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, ItalyDepartment of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, ItalyDepartment of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, ItalyDepartment of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, ItalyUniversity of Natural Resources and Life Sciences, 1180 Vienna, AustriaRegional Hospital, 87100 Cosenza, ItalyEndocrinology, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi-Nesima Hospital, 95122 Catania, ItalyDepartment of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, ItalyThe 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.http://www.mdpi.com/2073-4409/8/3/223cancer-associated fibroblastsGPERbreast cancerestrogenFGFR1FGF2 |
| spellingShingle | Maria Francesca Santolla Adele Vivacqua Rosamaria Lappano Damiano Cosimo Rigiracciolo Francesca Cirillo Giulia Raffaella Galli Marianna Talia Giuseppe Brunetti Anna Maria Miglietta Antonino Belfiore Marcello Maggiolini GPER Mediates a Feedforward FGF2/FGFR1 Paracrine Activation Coupling CAFs to Cancer Cells Toward Breast Tumor Progression Cells cancer-associated fibroblasts GPER breast cancer estrogen FGFR1 FGF2 |
| title | GPER Mediates a Feedforward FGF2/FGFR1 Paracrine Activation Coupling CAFs to Cancer Cells Toward Breast Tumor Progression |
| title_full | GPER Mediates a Feedforward FGF2/FGFR1 Paracrine Activation Coupling CAFs to Cancer Cells Toward Breast Tumor Progression |
| title_fullStr | GPER Mediates a Feedforward FGF2/FGFR1 Paracrine Activation Coupling CAFs to Cancer Cells Toward Breast Tumor Progression |
| title_full_unstemmed | GPER Mediates a Feedforward FGF2/FGFR1 Paracrine Activation Coupling CAFs to Cancer Cells Toward Breast Tumor Progression |
| title_short | GPER Mediates a Feedforward FGF2/FGFR1 Paracrine Activation Coupling CAFs to Cancer Cells Toward Breast Tumor Progression |
| title_sort | gper mediates a feedforward fgf2 fgfr1 paracrine activation coupling cafs to cancer cells toward breast tumor progression |
| topic | cancer-associated fibroblasts GPER breast cancer estrogen FGFR1 FGF2 |
| url | http://www.mdpi.com/2073-4409/8/3/223 |
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