ERβ decreases breast cancer cell survival by regulating the IRE1/XBP-1 pathway

Abstract

Unfolded protein response (UPR) is an adaptive reaction that allows cancer cells to survive endoplasmic reticulum (EnR) stress that is often induced in the tumor microenvironment because of inadequate vascularization. Previous studies report an association between activation of the UPR and reduced sensitivity to antiestrogens and chemotherapeutics in estrogen receptor α (ERα)-positive and triple-negative breast cancers, respectively. ERα has been shown to regulate the expression of a key mediator of the EnR stress response, the X-box-binding protein-1 (XBP-1). Although network prediction models have associated ERβ with the EnR stress response, its role as regulator of the UPR has not been experimentally tested. Here, upregulation of wild-type ERβ (ERβ1) or treatment with ERβ agonists enhanced apoptosis in breast cancer cells in the presence of pharmacological inducers of EnR stress. Targeting the BCL-2 to the EnR of the ERβ1-expressing cells prevented the apoptosis induced by EnR stress but not by non-EnR stress apoptotic stimuli indicating that ERβ1 promotes EnR stress-regulated apoptosis. Downregulation of inositol-requiring kinase 1α (IRE1α) and decreased splicing of XBP-1 were associated with the decreased survival of the EnR-stressed ERβ1-expressing cells. ERβ1 was found to repress the IRE1 pathway of the UPR by inducing degradation of IRE1α. These results suggest that the ability of ERβ1 to target the UPR may offer alternative treatment strategies for breast cancer.

Insufficient antibody validation challenges oestrogen receptor beta research

“…Thus, it is not inconceivable that the IP-MS detection of WDCP here indicates a true protein-protein interaction rather than unspecific binding. While PPZ0506 has been less used, 14C8 is the most referenced antibody for ERβ in Antibodypedia (http://www.antibodypedia.com/gene/11874/ESR2) and several previous reports find this antibody to work well414243444546. We, however, noted that not only did 14C8 stain tissues that lack ERβ when applied in IHC, it also generated a band of the expected size in WB of negative controls that could easily be mistaken for ERβ.…”

Estrogen Signaling as a Therapeutic Target in Neurodevelopmental Disorders

“…Estradiol has also been shown to exert anti-inflammatory activity on activated macrophages and microglia (Dodel et al, 1999;Bruce-Keller et al, 2000;Drew and Chavis, 2000;Vegeto et al, 2001Vegeto et al, , 2003Vegeto et al, , 2004. Estrogen is known to reduce endoplasmic reticulum stress, an inducer of inflammation, through a synovilin 1-dependent mechanism (Kooptiwut et al, 2014;Rajapaksa et al, 2015). It has been shown that ovariectomy is associated with changes in the peripheral immune response as evidenced by increased levels of inflammatory markers such as tumor necrosis factora, interleukin-1b, macrophage inflammatory protein-1, and macrophage colony-stimulating factor (Cenci et al, 2000;Benedusi et al, 2012).…”

Somatic loss of estrogen receptor beta and p53 synergize to induce breast tumorigenesis

“…More consistent evidence of the tumor-repressive activities of ERβ has been derived from in-vitro models of breast cancer. These include regulation of cellular response to DNA damage [5], induction of apoptosis [6], delayed cell cycle progression and inhibition of xenograft growth [7, 8], mesenchymal to epithelial transition, decreased cell migration/invasion and repression of oncogenic growth factor receptor and mutant p53 signaling [9–11]. …”