Anticipatory estrogen activation of the unfolded protein response is linked to cell proliferation and poor survival in estrogen receptor α-positive breast cancer

Recurrent estrogen receptor α (ERα)-positive breast and ovarian cancers are often therapy resistant. Using screening and functional validation, we identified BHPI, a potent noncompetitive small molecule ERα biomodulator that selectively blocks proliferation of drug-resistant ERα-positive breast and ovarian cancer cells. In a mouse xenograft model of breast cancer, BHPI induced rapid and substantial tumor regression. Whereas BHPI potently inhibits nuclear estrogen–ERα-regulated gene expression, BHPI is effective because it elicits sustained ERα-dependent activation of the endoplasmic reticulum (EnR) stress sensor, the unfolded protein response (UPR), and persistent inhibition of protein synthesis. BHPI distorts a newly described action of estrogen–ERα: mild and transient UPR activation. In contrast, BHPI elicits massive and sustained UPR activation, converting the UPR from protective to toxic. In ERα+ cancer cells, BHPI rapidly hyperactivates plasma membrane PLCγ, generating inositol 1,4,5-triphosphate (IP3), which opens EnR IP3R calcium channels, rapidly depleting EnR Ca2+ stores. This leads to activation of all three arms of the UPR. Activation of the PERK arm stimulates phosphorylation of eukaryotic initiation factor 2α (eIF2α), resulting in rapid inhibition of protein synthesis. The cell attempts to restore EnR Ca2+ levels, but the open EnR IP3R calcium channel leads to an ATP-depleting futile cycle, resulting in activation of the energy sensor AMP-activated protein kinase and phosphorylation of eukaryotic elongation factor 2 (eEF2). eEF2 phosphorylation inhibits protein synthesis at a second site. BHPI’s novel mode of action, high potency, and effectiveness in therapy-resistant tumor cells make it an exceptional candidate for further mechanistic and therapeutic exploration.

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TXNIP links anticipatory unfolded protein response to estrogen reprogramming glucose metabolism in breast cancer cells

Endocrinology ◽

10.1210/endocr/bqab212 ◽

2021 ◽

Author(s):

Yuanzhong Wang ◽

Shiuan Chen

Keyword(s):

Breast Cancer ◽

Cell Proliferation ◽

Glucose Metabolism ◽

Glucose Uptake ◽

Unfolded Protein Response ◽

Cancer Cells ◽

Warburg Effect ◽

Breast Cancer Cells ◽

Unfolded Protein ◽

Protein Response

Abstract Estrogen and estrogen receptor (ER) play a fundamental role in breast cancer. To adapt the rapid proliferation of ER+ breast cancer cells, estrogen increases glucose uptake and reprograms glucose metabolism. Meanwhile, estrogen/ER activates the anticipatory unfolded protein response (UPR) preparing cancer cells for the increased protein production required for subsequent cell proliferation. Here, we report that thioredoxin-interacting protein (TXNIP) is an important regulator of glucose metabolism in ER+ breast cancer cells, and estrogen/ER increases glucose uptake and reprograms glucose metabolism via activating anticipatory unfolded protein response (UPR) and subsequently repressing TXNIP expression. By using two widely used ER+ breast cancer cell lines MCF7 and T47D, we showed that MCF7 cells express high TXNIP levels and exhibit mitochondrial oxidative phosphorylation (OXPHOS) phenotype, while T47D cells express low TXNIP levels and display aerobic glycolysis (Warburg effect) phenotype. Knockdown of TXNIP promoted glucose uptake and Warburg effect, while forced overexpression of TXNIP inhibited glucose uptake and Warburg effect. We further showed that estrogen represses TXNIP expression and activates UPR sensor inositol-requiring enzyme 1 (IRE1) via ER in the breast cancer cells, and IRE1 activity is required for estrogen suppression of TXNIP expression and estrogen-induced cell proliferation. Together, our study suggests that TXNIP is involved in estrogen-induced glucose uptake and metabolic reprogramming in ER+ breast cancer cells, and links anticipatory UPR to estrogen reprogramming glucose metabolism.

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Rapid Induction of the Unfolded Protein Response and Apoptosis by Estrogen Mimic TTC-352 for the Treatment of Endocrine-Resistant Breast Cancer

Molecular Cancer Therapeutics ◽

10.1158/1535-7163.mct-20-0563 ◽

2020 ◽

Vol 20 (1) ◽

pp. 11-25

Author(s):

Balkees Abderrahman ◽

Philipp Y. Maximov ◽

Ramona F. Curpan ◽

Sean W. Fanning ◽

Jay S. Hanspal ◽

...

Keyword(s):

Breast Cancer ◽

Unfolded Protein Response ◽

Unfolded Protein ◽

Rapid Induction ◽

The Unfolded Protein Response ◽

Protein Response

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Comprehensive Analysis of the Unfolded Protein Response in Breast Cancer Subtypes

JCO Precision Oncology ◽

10.1200/po.16.00073 ◽

2017 ◽

pp. 1-9 ◽

Cited By ~ 4

Author(s):

Dadi Jiang ◽

Brandon Turner ◽

Jie Song ◽

Ruijiang Li ◽

Maximilian Diehn ◽

...

Keyword(s):

Breast Cancer ◽

Estrogen Receptor ◽

Patient Survival ◽

Gene Signature ◽

Comprehensive Analysis ◽

Breast Cancer Subtypes ◽

Cancer Subtypes ◽

Unfolded Protein ◽

The Unfolded Protein Response ◽

Protein Response

Purpose Triple-negative breast cancers (TNBCs) are associated with a worse prognosis and patients with TNBC have fewer therapeutic options than patients with non-TNBC. Recently, the IRE1α-XBP1 branch of the unfolded protein response (UPR) was implicated in TNBC prognosis on the basis of a relatively small patient population, suggesting the diagnostic and therapeutic value of this pathway in TNBCs. In addition, the IRE1α-XBP1 and hypoxia-induced factor 1 α (HIF1α) pathways have been identified as interacting partners in TNBC, suggesting a novel mechanism of regulation. To comprehensively evaluate and validate these findings, we investigated the relative activities and relevance to patient survival of the UPR and HIF1α pathways in different breast cancer subtypes in large populations of patients. Materials and Methods We performed a comprehensive analysis of gene expression and survival data from large cohorts of patients with breast cancer. The patients were stratified based on the average expression of the UPR or HIF1α gene signatures. Results We identified a strong positive association between the XBP1 gene signature and estrogen receptor–positive status or the HIF1α gene signature, as well as the predictive value of the XBP1 gene signature for survival of patients who are estrogen receptor negative, or have TNBC or HER2+. In contrast, another important UPR branch, the ATF4/CHOP pathway, lacks prognostic value in breast cancer in general. Activity of the HIF1α pathway is correlated with patient survival in all the subtypes evaluated. Conclusion These findings clarify the relevance of the UPR pathways in different breast cancer subtypes and underscore the potential therapeutic importance of the IRE1α-XBP1 branch in breast cancer treatment.

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KDM4B-regulated unfolded protein response as a therapeutic vulnerability in PTEN-deficient breast cancer

Journal of Experimental Medicine ◽

10.1084/jem.20180439 ◽

2018 ◽

Vol 215 (11) ◽

pp. 2833-2849 ◽

Cited By ~ 9

Author(s):

Wenyu Wang ◽

Gokce Oguz ◽

Puay Leng Lee ◽

Yi Bao ◽

Panpan Wang ◽

...

Keyword(s):

Breast Cancer ◽

Unfolded Protein Response ◽

Breast Cancers ◽

Akt Inhibitor ◽

Unfolded Protein ◽

Crucial Component ◽

Pi3k Inhibition ◽

Demethylase Activity ◽

The Unfolded Protein Response ◽

Protein Response

PTEN deficiency in breast cancer leads to resistance to PI3K–AKT inhibitor treatment despite aberrant activation of this signaling pathway. Here, we report that genetic depletion or small molecule inhibition of KDM4B histone demethylase activates the unfolded protein response (UPR) pathway and results in preferential apoptosis in PTEN-deficient triple-negative breast cancers (TNBCs). Intriguingly, this function of KDM4B on UPR requires its demethylase activity but is independent of its canonical role in histone modification, and acts through its cytoplasmic interaction with eIF2α, a crucial component of UPR signaling, resulting in reduced phosphorylation of this component. Targeting KDM4B in combination with PI3K inhibition induces further activation of UPR, leading to robust synergy in apoptosis. These findings identify KDM4B as a therapeutic vulnerability in PTEN-deficient TNBC that otherwise would be resistant to PI3K inhibition.

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