title: GPER signalling in both cancer-associated fibroblasts and breast cancer cells mediates a feedforward IL1β/IL1R1 response.
abstract: Cancer-associated fibroblasts (CAFs) contribute to the malignant aggressiveness through secreted factors like IL1β, which may drive pro-tumorigenic inflammatory phenotypes mainly acting via the cognate receptor named IL1R1. Here, we demonstrate that signalling mediated by the G protein estrogen receptor (GPER) triggers IL1β and IL1R1 expression in CAFs and breast cancer cells, respectively. Thereby, ligand-activation of GPER generates a feedforward loop coupling IL1β induction by CAFs to IL1R1 expression by cancer cells, promoting the up-regulation of IL1β/IL1R1 target genes such as PTGES, COX2, RAGE and ABCG2. This regulatory interaction between the two cell types induces migration and invasive features in breast cancer cells including fibroblastoid cytoarchitecture and F-actin reorganization. A better understanding of the mechanisms involved in the regulation of pro-inflammatory cytokines by GPER-integrated estrogen signals may be useful to target these stroma-cancer interactions.
authors.affiliation: Department of Pharmacy and Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: De Marco
authors.affiliation: Department of Pharmacy and Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy.
authors.forename: Rosamaria
authors.initials: R
authors.lastname: Lappano
authors.affiliation: Department of Pharmacy and Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy.
authors.forename: Ernestina Marianna
authors.initials: EM
authors.lastname: De Francesco
authors.affiliation: Department of Pharmacy and Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Cirillo
authors.affiliation: Department of Pharmacy and Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy.|Department of Cell Biology, Faculty of Sciences, and Institute of Genetics and Genomics of Geneva, University of Geneva, Geneva Switzerland.
authors.forename: Marco
authors.initials: M
authors.lastname: Pupo
authors.affiliation: Department of Pharmacy and Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Avino
authors.affiliation: Department of Pharmacy and Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy.
authors.forename: Adele
authors.initials: A
authors.lastname: Vivacqua
authors.affiliation: Breast Cancer Unit, Regional Hospital, 87100 Cosenza, Italy.
authors.forename: Sergio
authors.initials: S
authors.lastname: Abonante
authors.affiliation: Department of Cell Biology, Faculty of Sciences, and Institute of Genetics and Genomics of Geneva, University of Geneva, Geneva Switzerland.
authors.forename: Didier
authors.initials: D
authors.lastname: Picard
authors.affiliation: Department of Pharmacy and Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy.
authors.forename: Marcello
authors.initials: M
authors.lastname: Maggiolini
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D053573:Receptors, Interleukin-1 Type I / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C109584:GPER1 protein, human; C508590:IL1R1 protein, human; D053583:Interleukin-1beta; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled; D053573:Receptors, Interleukin-1 Type I