ESR1 and breast cancer: For example, ERK1/2 hyperactivation in breast cancer arises through multi-layered mechanisms, including receptor tyrosine kinase signaling via HER2 amplification or EGFR activation, ligand-dependent ERα non-genomic signaling (e.g., membrane-associated SRC/EGFR crosstalk), and epigenetic silencing of ERK1/2 phosphatases (DUSP1/DUSP6) (36–39).