GPER signalling in both cancer-associated fibroblasts and breast cancer cells mediates a feedforward IL1β/IL1R1 response

Cancer-associated fibroblasts (CAFs) contribute to the malignant aggressiveness through secreted factors like IL1 beta, 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 IL1 beta and IL1R1 expression in CAFs and breast cancer cells, respectively. Thereby, ligand-activation of GPER generates a feedforward loop coupling IL1 beta induction by CAFs to IL1R1 expression by cancer cells, promoting the up-regulation of IL1 beta/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 proinflammatory cytokines by GPER-integrated estrogen signals may be useful to target these stromacancer interactions.