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

Barua, David; Abbasi, Benazir; Gupta, Ananya; Gupta, Sanjeev

doi:10.1016/j.heliyon.2020.e05217

Cited by 4 publications

(6 citation statements)

References 30 publications

(57 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Indeed, expression of the XBP1s protein is elevated by estrogen stimulation in ER-positive breast cancer cells [ 22 , 24 , 25 ]. Further, XBP1s protein physically interacts with ER and enhances the estrogen-independent transactivational function of ER [ 12 , 26 ] which generates a positive feedback loop consisting of XBP1s and ER. This positive feedback loop generated by cross talk between estrogen signalling and UPR contributes to elevated co-expression of ER and XBP1 in ER-positive breast cancer [ 3 ].…”

Section: Discussionmentioning

confidence: 99%

RRM2 and CDC6 are novel effectors of XBP1-mediated endocrine resistance and predictive markers of tamoxifen sensitivity

Barua¹,

Sultana²,

Islam

et al. 2023

BMC Cancer

Self Cite

View full text Add to dashboard Cite

Background Endocrine-resistant breast cancers have elevated expression of XBP1, where it drives endocrine resistance by controlling the expression of its target genes. Despite the in-depth understanding of the biological functions of XBP1 in ER-positive breast cancer, effectors of endocrine resistance downstream of XBP1 are poorly understood. The aim of this study was to identify the XBP1-regulated genes contributing to endocrine resistance in breast cancer. Methods XBP1 deficient sub-clones in MCF7 cells were generated using the CRISPR-Cas9 gene knockout strategy and were validated using western blot and RT-PCR. Cell viability and cell proliferation were evaluated using the MTS assay and colony formation assay, respectively. Cell death and cell cycle analysis were determined using flow cytometry. Transcriptomic data was analysed to identify XBP1-regulated targets and differential expression of target genes was evaluated using western blot and qRT-PCR. Lentivirus and retrovirus transfection were used to generate RRM2 and CDC6 overexpressing clones, respectively. The prognostic value of the XBP1-gene signature was analysed using Kaplan–Meier survival analysis. Results Deletion of XBP1 compromised the upregulation of UPR-target genes during conditions of endoplasmic reticulum (EnR) stress and sensitized cells to EnR stress-induced cell death. Loss of XBP1 in MCF7 cells decreased cell growth, attenuated the induction of estrogen-responsive genes and sensitized them to anti-estrogen agents. The expression of cell cycle associated genes RRM2, CDC6, and TOP2A was significantly reduced upon XBP1 deletion/inhibition in several ER-positive breast cancer cells. Expression of RRM2, CDC6, and TOP2A was increased upon estrogen stimulation and in cells harbouring point-mutants (Y537S, D538G) of ESR1 in steroid free conditions. Ectopic expression of RRM2 and CDC6 increased cell growth and reversed the hypersensitivity of XBP1 KO cells towards tamoxifen conferring endocrine resistance. Importantly, increased expression of XBP1-gene signature was associated with poor outcome and reduced efficacy of tamoxifen treatment in ER-positive breast cancer. Conclusions Our results suggest that RRM2 and CDC6 downstream of XBP1 contribute to endocrine resistance in ER-positive breast cancer. XBP1-gene signature is associated with poor outcome and response to tamoxifen in ER-positive breast cancer.

show abstract

Section: Discussionmentioning

confidence: 99%

RRM2 and CDC6 are novel effectors of XBP1-mediated endocrine resistance and predictive markers of tamoxifen sensitivity

Barua¹,

Sultana²,

Islam

et al. 2023

BMC Cancer

Self Cite

View full text Add to dashboard Cite

show abstract

“…The crosstalk between XBP1s and estrogen signalling creates a positive feedback loop that results in increased expression of XBP1 in ER-positive breast cancer [ 23 ]. XBP1s can contribute to endocrine resistance by enhancing the transcriptional activity of point mutants (Y537S, D538G) and fusion mutants (ESR1-YAP1, ESR1-DAB2) of ESR1 [ 22 ]. Knockdown of XBP1 in genome edited MCF7 cells expressing Y537S mutant reduced their growth and re-sensitised them to endocrine therapy [ 22 ].…”

Section: Discussionmentioning

confidence: 99%

“…XBP1s can contribute to endocrine resistance by enhancing the transcriptional activity of point mutants (Y537S, D538G) and fusion mutants (ESR1-YAP1, ESR1-DAB2) of ESR1 [ 22 ]. Knockdown of XBP1 in genome edited MCF7 cells expressing Y537S mutant reduced their growth and re-sensitised them to endocrine therapy [ 22 ]. Furthermore, NCOA3 RRM2 and CDC6 are mediators of endocrine resistance downstream of XBP1s in ER-positive breast cancer [ 20 , 24 ].…”

Section: Discussionmentioning

confidence: 99%

“…The XBP1s contributes to the development of endocrine-resistant breast cancer by upregulating the expression of BCL2, p65/RelA, NCOA3, RRM2, CDC6, and TOP2A [ 16 , 20 , 21 , 22 , 23 , 24 ]. It is likely that other yet unidentified XBP1-regulated genes contribute to ligand-independent growth and endocrine-resistant disease in ER-positive breast cancer.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

miRNA-378 Is Downregulated by XBP1 and Inhibits Growth and Migration of Luminal Breast Cancer Cells

Arabkari,

Barua,

Hossain

et al. 2023

IJMS

Self Cite

View full text Add to dashboard Cite

X-box binding protein 1 (XBP1) is a transcription factor that plays a crucial role in the unfolded protein response (UPR), a cellular stress response pathway involved in maintaining protein homeostasis in the endoplasmic reticulum (EnR). While the role of XBP1 in UPR is well-characterised, emerging evidence suggests its involvement in endocrine resistance in breast cancer. The transcriptional activity of spliced XBP1 (XBP1s) is a major component of its biological effects, but the targets of XBP1s in estrogen receptor (ER)-positive breast cancer are not well understood. Here, we show that the expression of miR-378 and PPARGC1B (host gene of miR-378) is downregulated during UPR. Using chemical and genetic methods, we show that XBP1s is necessary and sufficient for the downregulation of miR-378 and PPARGC1B. Our results show that overexpression of miR-378 significantly suppressed cell growth, colony formation, and migration of ER-positive breast cancer cells. Further, we found that expression of miR-378 sensitised the cells to UPR-induced cell death and anti-estrogens. The expression of miR-378 and PPARGC1B was downregulated in breast cancer, and higher expression of miR-378 is associated with better outcomes in ER-positive breast cancer. We found that miR-378 upregulates the expression of several genes that regulate type I interferon signalling. Analysis of separate cohorts of breast cancer patients showed that a gene signature derived from miR-378 upregulated genes showed a strong association with improved overall and recurrence-free survival in breast cancer. Our results suggest a growth-suppressive role for miR-378 in ER-positive breast cancer where downregulation of miR-378 by XBP1 contributes to endocrine resistance in ER-positive breast cancer.

show abstract

“…These pathways transfer information on the protein folding status in the ER to the cytosol and nucleus to restore protein-folding capacity. 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 ].…”

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

View full text Add to dashboard Cite

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.

show abstract

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

Cited by 4 publications

References 30 publications

RRM2 and CDC6 are novel effectors of XBP1-mediated endocrine resistance and predictive markers of tamoxifen sensitivity

RRM2 and CDC6 are novel effectors of XBP1-mediated endocrine resistance and predictive markers of tamoxifen sensitivity

miRNA-378 Is Downregulated by XBP1 and Inhibits Growth and Migration of Luminal Breast Cancer Cells

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

Contact Info

Product

Resources

About