Although SERMs, SERDs, and AIs may be involved in different mechanisms of ER down-regulation in BC cells, the core mechanisms that contribute to ET resistance are estrogen hypersensitivity, ER changes (i.e., receptor loss, mutations, or gene expression changes), intracellular environmental molecular changes (i.e., PR loss, changes in the expression of cofactors), and increased molecular cross-talking between ER and growth factor receptor signaling pathways [21] leading to the dysregulation of PI3K-PTEN/AKT/mTOR, RAS/MEK/MAPK, and NF-κB pathways [21]. The gene discussed is ESR1; the disease is breast cancer.