Fig. 8

Illustration depicting the role of G protein-coupled estrogen receptor and β1-integrin in the epithelial-mesenchymal transition process induced by cancer-associated fibroblasts. Long-term exposure to tamoxifen promotes the translocation of G protein-coupled estrogen receptor (GPER) to the cell membrane, which enhances the crosstalk between GPER and epidermal growth factor receptor (EGFR). The Ga subunit of GPER is responsible for the increase in cAMP generation in breast cancer cells and cAMP attenuates ERK1/2 activity by suppressing protein kinase A (PKA) on Raf, whereas cAMP production triggered by GPER is disorganized upon acquisition of tamoxifen resistance leading to the increased activation of ERK1/2. Tamoxifen, as an agonist for GPER, stimulates the induction of β1-integrin expression through the GPER/EGFR/ERK signaling pathway. Upregulation of β1-integrin is accompanied by the activation of the β1-integrin signaling pathway, which is measured by FAK and Src activity. Conditioned medium (CM) produced by cancer-associated fibroblasts (CAFs) induces epithelial-mesenchymal transition (EMT) through the activation of PI3K/AKT, with the involvement of β1-integrin. Targeted therapy with β1-integrin could reverse the stimulatory effect of CAFs in the tumor microenvironment on cell motility. ECM, extracellular matrix; ITGB1, β1-integrin; MMP, matrix metalloproteinase