ESR1 and breast cancer: For example, CAFs activate the JAK-STAT3 and PI3K-Akt pathways in breast cancer cells by secreting IL-6, inducing the upregulation of epithelial−mesenchymal transition and E3 ubiquitin ligase complex function, and targeting the degradation of estrogen receptor alpha through the ubiquitin proteasome pathway, thereby leading to tamoxifen resistance in breast cancer cells (49).