Targeting the IRE1-XBP1 axis to overcome endocrine resistance in breast cancer: Opportunities and challenges

Barua, David; Gupta, Ananya; Gupta, Sanjeev

doi:10.1016/j.canlet.2020.05.020

Cited by 42 publications

(34 citation statements)

References 92 publications

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“…Several studies have shown that activation of estrogen-responsive genes is a common feature of endocrine-resistant ER-positive breast cancers harbouring ESR1 mutations [ 29 ]. The expression of XBP1s is increased upon E2-stimulation, which in turn, enhances ER-dependent transcriptional activity [ 22 ]. We found the increased expression of XBP1 in cells harbouring Y537S and D538G mutations.…”

Section: Discussionmentioning

confidence: 99%

“…Over expression of XBP1s in MCF7 breast cancer cells causes estrogen-independent growth and resistance to endocrine therapy [ 21 ]. The endocrine-resistant breast cancers show increased expression of XBP1s [ 22 ]. The obligate requirement of IRE1-dependent splicing to generate XBP1s has been exploited to generate chemical inhibitors to selectively block the production of XBP1s protein [ 22 ].…”

Section: Introductionmentioning

confidence: 99%

“…The endocrine-resistant breast cancers show increased expression of XBP1s [ 22 ]. The obligate requirement of IRE1-dependent splicing to generate XBP1s has been exploited to generate chemical inhibitors to selectively block the production of XBP1s protein [ 22 ]. Several inhibitors have been reported that selectively inhibit the RNase activity of IRE1 and blocks the splicing of XBP1 mRNA [ 22 ].…”

Section: Introductionmentioning

confidence: 99%

“…The obligate requirement of IRE1-dependent splicing to generate XBP1s has been exploited to generate chemical inhibitors to selectively block the production of XBP1s protein [ 22 ]. Several inhibitors have been reported that selectively inhibit the RNase activity of IRE1 and blocks the splicing of XBP1 mRNA [ 22 ]. Blocking XBP1s expression by STF-083010 has been shown to re-sensitize the tamoxifen-resistant MCF7 cells in a xenograft model [ 23 ].…”

Section: Introductionmentioning

confidence: 99%

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XBP1 increases transactivation of somatic mutants of ESR1 and loss of XBP1 reverses endocrine resistance conferred by gain-of-function Y537S ESR1 mutation

Barua

Abbasi

Gupta

et al. 2020

Heliyon

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Somatic mutations of the estrogen receptor 1 gene (ESR1) is an emerging mechanism of acquired resistance to endocrine therapy in hormonal breast cancers. Hotspot point mutations in the ligand- binding domain of estrogen receptor α (ER) and genomic rearrangements producing ESR1 fusion genes are the two major types of mutations that are associated with endocrine resistance. The crosstalk between X-box binding protein 1 (XBP1), a key transcription factor of the unfolded protein response (UPR) and ER signalling creates a positive feedback loop that results in increased expression of XBP1 in ER-positive breast cancer. Here we report that XBP1 co-operated with point mutants (Y537S, D538G) and fusion mutants (ESR1-YAP1, ESR1-DAB2) of ESR1 to increase their transcriptional activity. XBP1 was required for optimal expression of estrogen-regulated genes, and up to 40% of XBP1-dependent genes were estrogen-responsive genes. Knockdown of XBP1 in genome-edited MCF7 cells expressing Y537S mutant reduced their growth, re-sensitized them to anti-estrogens and attenuated the constitutive and estrogen-stimulated expression of estrogen-regulated genes. Our study provides a rationale for overcoming endocrine resistance in breast cancers expressing ESR1 mutation by combining the XBP1 targeting agents with anti-estrogen agents.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

XBP1 increases transactivation of somatic mutants of ESR1 and loss of XBP1 reverses endocrine resistance conferred by gain-of-function Y537S ESR1 mutation

Barua

Abbasi

Gupta

et al. 2020

Heliyon

Self Cite

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“…Binding of the ER chaperone-binding immunoglobulin protein (BiP), also known as GRP-78 or heat shock 70 kDa protein 5 (HSPA5), to IRE1α causes its deactivation [4,5]. Under ER stress, BiP preferentially binds to mis-folded proteins and subsequently is released from PERK and IRE1, which initiates these proteins' dimerization [6]. Recent studies demonstrated a role for ER stress in fibrosis in multiple organs, including the lungs [1,7].…”

Section: Introductionmentioning

confidence: 99%

The ER Stress/UPR Axis in Chronic Obstructive Pulmonary Disease and Idiopathic Pulmonary Fibrosis

Aghaei

Dastghaib

Aftabi

et al. 2020

Life

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Cellular protein homeostasis in the lungs is constantly disrupted by recurrent exposure to various external and internal stressors, which may cause considerable protein secretion pressure on the endoplasmic reticulum (ER), resulting in the survival and differentiation of these cell types to meet the increased functional demands. Cells are able to induce a highly conserved adaptive mechanism, known as the unfolded protein response (UPR), to manage such stresses. UPR dysregulation and ER stress are involved in numerous human illnesses, such as metabolic syndrome, fibrotic diseases, and neurodegeneration, and cancer. Therefore, effective and specific compounds targeting the UPR pathway are being considered as potential therapies. This review focuses on the impact of both external and internal stressors on the ER in idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD) and discusses the role of the UPR signaling pathway activation in the control of cellular damage and specifically highlights the potential involvement of non-coding RNAs in COPD. Summaries of pathogenic mechanisms associated with the ER stress/UPR axis contributing to IPF and COPD, and promising pharmacological intervention strategies, are also presented.

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Microfluidic Synthesis of Carrier‐Free Full‐Active Metal‐Phenolic Nanocapsules for Tumor Chemo‐Chemodynamic‐Immune Therapy

Yang,

Zhan,

Shen

et al. 2024

Adv Funct Materials

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Development of carrier‐free full‐active nanoplatforms to exert efficient tumor therapeutics and prevent tumor recurrence remains to be a challenging task. Herein, a microfluidic synthesis of self‐assembled carrier‐free gossypol (Gos)‐iron ion (Fe3+)‐toyocamycin (Toy) nanocapsules (GFT NCs) is developed for tumor magnetic resonance (MR) imaging and chemo‐chemodynamic‐immune therapy. The constructed GFT NCs with an average diameter of 101.9 nm display desirable colloidal stability, uniformity, pH‐responsive drug release profile, and enhanced r1 relaxivity (3.71 mm−1s−1) under an acidic condition. The NCs‐mediated co‐delivery of Gos, Fe3+, and Toy induces apparent immunogenic cell death by leveraging a combination of Gos‐induced mitochondrial dysfunction, Fe3+‐mediated chemodynamic therapy, and Toy‐amplified endoplasmic reticulum stress, thus efficiently inhibiting tumor growth and metastasis while triggering a potent antitumor immunity. When combined with programmed cell death ligand 1 antibody, the GFT NCs significantly enhance immune activation and establish tumor‐specific immune memory effects, thereby preventing tumor recurrence. Compared to Magnevist, a commercial T1 MR imaging contrast agent, the GFT NCs offer superior tumor T1‐weighted MR imaging at equivalent Fe or Gd concentrations in vivo. The developed GFT NCs represent a potential carrier‐free full‐active nanomedicine formulation for multifaceted and enhanced immunotherapy across diverse tumor types.

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Targeting the IRE1-XBP1 axis to overcome endocrine resistance in breast cancer: Opportunities and challenges

Cited by 42 publications

References 92 publications

XBP1 increases transactivation of somatic mutants of ESR1 and loss of XBP1 reverses endocrine resistance conferred by gain-of-function Y537S ESR1 mutation

XBP1 increases transactivation of somatic mutants of ESR1 and loss of XBP1 reverses endocrine resistance conferred by gain-of-function Y537S ESR1 mutation

The ER Stress/UPR Axis in Chronic Obstructive Pulmonary Disease and Idiopathic Pulmonary Fibrosis

Microfluidic Synthesis of Carrier‐Free Full‐Active Metal‐Phenolic Nanocapsules for Tumor Chemo‐Chemodynamic‐Immune Therapy

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