Studies on estrogen-receptor-deficient breast cancer cells and peritumoral fibroblast cells confirmed that estradiol acts as a G-protein-coupled estrogen receptor (GPER) ligand and induces SIRT1 expression by rapid activation of the EGFR (epidermal growth factor receptor)/ERK (extracellular-signal-regulated kinase)/c-fos/AP-1 (activator protein 1) pathway. This evidence concerns the gene FOS and breast cancer.