Estrogen‐independent tumors and cells exhibit therapeutic sensitivity to ER reactivation via E2 treatment or anti‐estrogen withdrawal. (A–C) Ovariectomized NSG (A) or BALB/cJ (B, C) mice were implanted s.c. with ~ 8‐mm3 fragments of serially transplanted WHIM16 patient‐derived xenografts (A), C7‐2‐HI murine allografts (B), or C4‐HI murine allografts (C). When tumors reached ~ 400 mm3, mice were randomized to sham surgery or s.c. implantation with an E2 pellet. Tumor volume is presented as mean + SD of % change from baseline on the day of E2 supplementation (Week 0). Groups were compared by linear mixed modeling. (D) MCF‐7 and LTED cells were cultured in hormone‐depleted medium ± E2 for 4 weeks; then, cells were fixed and stained with crystal violet for colony quantification using imagej. (E) MCF‐7 and FR cells seeded at low density were treated ± fulv. After 4 weeks, colonies were quantified as in (D). In (D, E), data are shown as mean of triplicates + SD relative to parental control. *P ≤ 0.05 by t‐test.