ESR1 and breast cancer: Studies have shown that advanced and metastatic ER+ breast cancers can develop endocrine resistance through various mechanisms, such as mutations in the ER-alpha gene, amplification/overexpression of epidermal growth factor and fibroblast growth factor receptor family genes, and activation of downstream signaling via the PI3K/AKT/mTOR signaling pathway (Musgrove and Sutherland, 2009; Clarke et al., 2015).