ESR1 and cancer: As they manifest inter-tumor heterogeneity, breast tumors are categorized in four groups that are differently treated in the clinic, based on the expression of estrogen receptors (ERs), progesterone receptors (PRs) and HER2: luminal-A cancers, where tumors express ER/PR and are HER2-negative (HER2−); luminal-B tumors that are positive for ER/PR and demonstrate HER2 amplification (HER2+) or are ki67-high; HER2+ tumors that do not express ER/PR and demonstrate HER2 over-expression; and triple-negative BCs (TNBCs) that lack the expression of the three receptors: ER, PR and HER2 (11–13).