For instance, mutations in ESR1 are observed in approximately 20% of recurrent ER+ breast cancers following long-term treatment with AIs or tamoxifen [9,17]; mutations in oncogenic pathways PI3K (including PIK3CA, PTEN, and AKT1) and MAPK (including NF1, KRAS/NRAS/HRAS, BRAF, and MAP2K1) are also frequently observed and endow endocrine resistance in breast cancer [9,17,25,26]. Here, MAP2K1 is linked to breast cancer.