ESR1 and breast cancer: For instance, Beatson reported a connection between estrogen and BC in 1986.[38] Similarly, further studies proved that estrogen binds to ERs and directly interacts with key signaling molecules (Shc) and membrane receptors (such as EGFR, ESR1, and IGFR) to activate the PI3K/AKT pathways, thereby promoting the proliferation and survival of tumor cells,[39] The Shc–EGFR complex (GO:0070435) revealed by GO enrichment analysis in our study supports this finding.