The therapeutic uses of aromatase inhibitors (AI) and GnRH agonists that limit estrogen production, tamoxifen, a selective estrogen receptor modulator (SERM), and fulvestrant, a selective ER downregulator (SERD) have resulted in significant improvements in survival outcomes for patients with ER+ breast cancer via ER-alpha (ESR1) mutation, growth factor receptor signaling, as well as PI3K/Akt/mTOR, CDK4/6, and epigenetic and immunological checkpoints as resistance mechanisms [148]. This evidence concerns the gene ESR1 and breast cancer.