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Updated: Jan 30, 2026
Profiling of Estrogen-regulated MicroRNAs in Breast Cancer Cells
Published on: February 21, 2014
Estrogen-Induced Apoptosis in Breast Cancers Is Phenocopied by Blocking Dephosphorylation of Eukaryotic Initiation
Surojeet Sengupta1, Catherine M Sevigny2, Poulomi Bhattacharya3
1Department of Oncology, Georgetown-Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington D.C. ss972@georgetown.edu.
Abstract:
Approximately 30% of aromatase-inhibitor-resistant, estrogen receptor-positive patients with breast cancer benefit from treatment with estrogen. This enigmatic estrogen action is not well understood and how it occurs remains elusive. Studies indicate that the unfolded protein response and apoptosis pathways play important roles in mediating estrogen-triggered apoptosis. Using MCF7:5C cells, which mimic aromatase inhibitor resistance, and are hypersensitive to estrogen as evident by induction of apoptosis, we define increased global protein translational load as the trigger for estrogen-induced apoptosis. The protein kinase RNA-like endoplasmic reticulum kinase pathway was activated followed by increased phosphorylation of eukaryotic initiation factor-2 alpha (eIF2α). These actions block global protein translation but preferentially allow high expression of specific transcription factors, such as activating transcription factor 4 and C/EBP homologous protein that facilitate apoptosis. Notably, we recapitulated this phenotype of MCF7:5C in two other endocrine therapy-resistant cell lines (MCF7/LCC9 and T47D:A18/4-OHT) by increasing the levels of phospho-eIF2α using salubrinal to pharmacologically inhibit the enzymes responsible for dephosphorylation of eIF2α, GADD34, and CReP. RNAi-mediated ablation of these genes induced apoptosis that used the same signaling as salubrinal treatment. Moreover, combining 4-hydroxy tamoxifen with salubrinal enhanced apoptotic potency. IMPLICATIONS: These results not only elucidate the mechanism of estrogen-induced apoptosis but also identify a drugable target for potential therapeutic intervention that can mimic the beneficial effect of estrogen in some breast cancers.
Insights
Estrogen triggers apoptosis in resistant breast cancer cells by increasing protein load, activating the unfolded protein response, and inhibiting protein translation. This mechanism offers a potential therapeutic target for endocrine therapy resistance.
Area of Science:
- Oncology
- Molecular Biology
- Endocrinology
Background:
- Approximately 30% of patients with estrogen receptor-positive breast cancer resistant to aromatase inhibitors benefit from estrogen treatment.
- The mechanism behind this beneficial estrogen action in resistant breast cancer remains poorly understood.
- The unfolded protein response and apoptosis pathways are implicated in estrogen-mediated cell death.
Purpose of the Study:
- To elucidate the mechanism of estrogen-induced apoptosis in endocrine therapy-resistant breast cancer.
- To identify potential therapeutic targets for overcoming aromatase inhibitor resistance.
Main Methods:
- Utilized MCF7:5C cells, a model for aromatase inhibitor resistance and estrogen hypersensitivity.
- Investigated the role of global protein translational load and the unfolded protein response (UPR) pathway.
- Examined the activation of protein kinase RNA-like endoplasmic reticulum kinase (PERK) and eukaryotic initiation factor-2 alpha (eIF2α) phosphorylation.
- Validated findings in other resistant cell lines (MCF7/LCC9, T47D:A18/4-OHT) using salubrinal and RNA interference (RNAi).
Main Results:
- Increased global protein translational load was identified as the trigger for estrogen-induced apoptosis.
- Activation of the PERK pathway led to eIF2α phosphorylation, blocking global translation but allowing pro-apoptotic transcription factors (ATF4, CHOP) expression.
- Pharmacological inhibition of eIF2α dephosphorylation (GADD34, CReP) using salubrinal mimicked the apoptotic phenotype in resistant cell lines.
- RNAi-mediated ablation of GADD34 and CReP induced apoptosis via similar signaling pathways.
- Combination therapy with 4-hydroxy tamoxifen and salubrinal enhanced apoptosis.
Conclusions:
- Estrogen-induced apoptosis in resistant breast cancer is mediated by increased protein load, UPR activation, and selective protein translation inhibition.
- The PERK/eIF2α/ATF4/CHOP signaling axis is crucial for this apoptotic process.
- Inhibition of eIF2α dephosphorylation represents a druggable target for overcoming endocrine therapy resistance in breast cancer.
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