ERβ decreases breast cancer cell survival by regulating the IRE1/XBP-1 pathway
G Rajapaksa1, F Nikolos1, I Bado1
1Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX, USA.
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.
Insights
Estrogen receptor beta (ERβ1) promotes cancer cell death during endoplasmic reticulum (ER) stress by inhibiting the unfolded protein response (UPR). This suggests ERβ1 as a potential therapeutic target for breast cancer treatment.
Area of Science:
- Oncology
- Molecular Biology
- Endocrinology
Background:
- Cancer cells utilize the unfolded protein response (UPR) to survive endoplasmic reticulum (ER) stress, common in tumor microenvironments.
- Estrogen receptor alpha (ERα) is linked to UPR regulation and impacts breast cancer treatment sensitivity.
- Estrogen receptor beta (ERβ) has been computationally linked to ER stress, but its direct role in UPR remains uninvestigated.
Purpose of the Study:
- To investigate the role of estrogen receptor beta (ERβ) in regulating the unfolded protein response (UPR) and its impact on breast cancer cell survival under ER stress.
- To determine if ERβ can modulate ER stress-induced apoptosis and identify the underlying molecular mechanisms.
Main Methods:
- Upregulation of wild-type ERβ (ERβ1) and treatment with ERβ agonists in breast cancer cells.
- Induction of ER stress using pharmacological agents.
- Assessment of apoptosis and cell survival.
- Investigation of BCL-2 targeting to the ER.
- Analysis of inositol-requiring kinase 1α (IRE1α) and X-box-binding protein-1 (XBP-1) splicing.
- Evaluation of IRE1α degradation.
Main Results:
- ERβ1 upregulation or ERβ agonist treatment enhanced apoptosis in breast cancer cells experiencing ER stress.
- ERβ1 was found to promote ER stress-regulated apoptosis, independent of non-ER stress stimuli.
- ERβ1 expression led to decreased survival of ER-stressed cells, associated with reduced IRE1α levels and XBP-1 splicing.
- ERβ1 actively repressed the IRE1 pathway of the UPR by inducing IRE1α degradation.
Conclusions:
- Estrogen receptor beta 1 (ERβ1) plays a critical role in regulating the UPR by inhibiting the IRE1α/XBP-1 pathway.
- ERβ1 promotes ER stress-induced apoptosis in breast cancer cells, suggesting its potential as a therapeutic target.
- Targeting ERβ1 and its interaction with the UPR offers novel therapeutic strategies for breast cancer treatment.
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