Estrogen therapy induces an unfolded protein response to drive cell death in ER+ breast cancer

Estrogens have been shown to elicit anticancer effects against estrogen receptor α (ER)‐positive breast cancer. We sought to determine the mechanism underlying the therapeutic response. Response to 17β‐estradiol was assessed in ER+ breast cancer models with resistance to estrogen deprivation: WHIM16 patient‐derived xenografts, C7‐2‐HI and C4‐HI murine mammary adenocarcinomas, and long‐term estrogen‐deprived MCF‐7 cells. As another means to reactivate ER, the anti‐estrogen fulvestrant was withdrawn from fulvestrant‐resistant MCF‐7 cells. Transcriptional, growth, apoptosis, and molecular alterations in response to ER reactivation were measured. 17β‐estradiol treatment and fulvestrant withdrawal induced transcriptional activation of ER, and cells adapted to estrogen deprivation or fulvestrant were hypersensitive to 17β‐estradiol. ER transcriptional response was followed by an unfolded protein response and apoptosis. Such apoptosis was dependent upon the unfolded protein response, p53, and JNK signaling. Anticancer effects were most pronounced in models exhibiting genomic amplification of the gene encoding ER (ESR1), suggesting that engagement of ER at high levels is cytotoxic. These data indicate that long‐term adaptation to estrogen deprivation or ER inhibition alters sensitivity to ER reactivation. In such adapted cells, 17β‐estradiol treatment and anti‐estrogen withdrawal hyperactivate ER, which drives an unfolded protein response and subsequent growth inhibition and apoptosis. 17β‐estradiol treatment should be considered as a therapeutic option for anti‐estrogen‐resistant disease, particularly in patients with tumors harboring ESR1 amplification or ER overexpression. Furthermore, therapeutic strategies that enhance an unfolded protein response may increase the therapeutic effects of ER reactivation.