SpliceArray Profiling of Breast Cancer Reveals a Novel Variant of <i>NCOR2/SMRT</i> That Is Associated with Tamoxifen Resistance and Control of <i>ERα</i> Transcriptional Activity

Zhang, Luduo; Gong, Chun; Lau, Samantha Ly; Yang, Nan; Wong, Oscar Gee‐Wan; Cheung, Annie N.Y.; Tsang, Janice; Chan, Kelvin Yuen-Kwong; Khoo, Ui‐Soon

doi:10.1158/0008-5472.can-12-2241

Cited by 31 publications

(50 citation statements)

References 32 publications

(23 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Notably, the nuclear receptor co-repressor 2 (NCOR2) has been demonstrated to inhibit NRF2 transcription upon activation of glucocorticoid receptor [27]. Our group has previously identified a novel splice variant of NCOR2, BQ323636.1 (called BQ in short) from SpliceArray profiling of breast cancer [28]. BQ is derived from alternative splicing of NCOR2.…”

Section: Introductionmentioning

confidence: 99%

A Splice Variant of NCOR2, BQ323636.1, Confers Chemoresistance in Breast Cancer by Altering the Activity of NRF2

Leung

Tsoi

Gong

et al. 2020

Cancers

Self Cite

View full text Add to dashboard Cite

Breast cancer is the most common type of female cancer. Reactive oxygen species (ROS) are vital in regulating signaling pathways that control cell survival and cell proliferation. Chemotherapeutic drugs such as anthracyclines induce cell death via ROS induction. Chemoresistance development is associated with adaptive response to oxidative stress. NRF2 is the main regulator of cytoprotective response to oxidative stress. NRF2 can enhance cell growth, antioxidant expression, and chemoresistance by providing growth advantage for malignant cells. Previously, we identified BQ323636.1 (BQ), a novel splice variant of nuclear co-repressor NCOR2, which can robustly predict tamoxifen resistance in primary breast cancer. In this study, we found that BQ was overexpressed in epirubicin-resistant cells and demonstrated that BQ overexpression could reduce the levels of epirubicin-induced ROS and confer epirubicin resistance. In vivo analysis using tissue microarray of primary breast cancer showed direct correlation between BQ expression and chemoresistance. In vitro experiments showed BQ could modulate NRF2 transcriptional activity and upregulate antioxidants. Luciferase reporter assays showed that although NCOR2 repressed the transcriptional activity of NRF2, the presence of BQ reduced this repressive activity. Co-immunoprecipitation confirmed that NCOR2 could bind to NRF2 and that this interaction was compromised by BQ overexpression, leading to increased transcriptional activity in NRF2. Our findings suggest BQ can regulate the NRF2 signaling pathway via interference with NCOR2 suppressive activity and reveals a novel role for BQ as a modulator of chemoresistance in breast cancer.

show abstract

Section: Introductionmentioning

confidence: 99%

A Splice Variant of NCOR2, BQ323636.1, Confers Chemoresistance in Breast Cancer by Altering the Activity of NRF2

Leung

Tsoi

Gong

et al. 2020

Cancers

Self Cite

View full text Add to dashboard Cite

show abstract

“…Loss of VDR leads to increased incidence, higher tumor burden, and more aggressive phenotypes of cancer [60], and VDR polymorphisms are associated with breast cancer [61]. SMRT also known as NCOR2 is associated with tamoxifen resistance of breast cancer and control of ERα transcriptional activity [62]. Interestingly, seven gene sets related to the MAPK pathway and three gene sets consisting of genes with high-CpGdensity promoters bearing histone H3 trimethylation at K27 (H3K27me3) and possible dimethylation at K4 (H3K4me2) were enriched in our network modules.…”

Section: Discussionmentioning

confidence: 99%

Identification of epigenetic modulators in human breast cancer by integrated analysis of DNA methylation and RNA-Seq data

2018

View full text Add to dashboard Cite

Human tumors undergo massive changes in DNA methylation. Recent studies showed that site-specific methylation of CpG sites is determined by the DNA sequence context surrounding the CpG site, which alludes to a possible mechanism for site-specific aberrant DNA methylation in cancer through DNA-binding proteins. In this paper, DNA methylation data and RNA-Seq data of breast tumors and normal tissues in the database of The Cancer Genome Atlas (TCGA) were integrated with information of DNA motifs in seven databases to find DNA-binding proteins and their binding motifs that were involved in aberrant DNA methylation in breast cancer. A total of 42,850 differentially methylated regions (DMRs) that include 77,298 CpG sites were detected in breast cancer. One hundred eight DNA motifs were found to be enriched in DMRs, and 109 genes encoding proteins binding to these motifs were determined. Based on these motifs and genes, 63 methylation modulator genes were identified to regulate differentially methylated CpG sites in breast cancer. A network of these 63 modulator genes and 645 transcription factors was constructed, and 20 network modules were determined. A number of pathways and gene sets related to breast cancer were found to be enriched in these network modules. The 63 methylation modulator genes identified may play an important role in aberrant methylation of CpG sites in breast cancer. They may help to understand site-specific dysregulation of DNA methylation and provide epigenetic markers for breast cancer.

show abstract

“…MCF-7 and ZR-75 are ERα + tamoxifen sensitive cell lines [24,25], exhibiting reduced cell viability on tamoxifen treatment. However, once eIF4E was overexpressed in these cell lines, the effect of tamoxifen on cell viability was compromised ( Fig.…”

Section: Eif4e Overexpression Altered Tamoxifen Response In Breast Camentioning

confidence: 99%

“…AK-47 and LCC2 were a kind gift from Prof. Robert Clarke (Georgetown University, Washington, D.C). All cell lines were authenticated by STR profiling in 2013 [25]. All cell lines were tested to confirm no mycoplasma contamination.…”

Section: Cell Culturementioning

confidence: 99%

See 1 more Smart Citation

Phosphorylation independent eIF4E translational reprogramming of selective mRNAs determines tamoxifen resistance in breast cancer

et al. 2020

Self Cite

View full text Add to dashboard Cite

Eukaryotic translation initiation factor 4E (eIF4E) selectively promotes translation of mRNAs with atypically long and structured 5′-UTRs and has been implicated in drug resistance. Through genome-wide transcriptome and translatome analysis we revealed eIF4E overexpression could promote cellular activities mediated by ERα and FOXM1 signalling pathways. Whilst eIF4E overexpression could enhance the translation of both ERα and FOXM1, it also led to enhanced transcription of FOXM1. Polysome fractionation experiments confirmed eIF4E could modulate the translation of ERα and FOXM1 mRNA. The enhancement of FOXM1 transcription was contingent upon the presence of ERα, and it was the high levels of FOXM1 that conferred Tamoxifen resistance. Furthermore, tamoxifen resistance was conferred by phosphorylation independent eIF4E overexpression. Immunohistochemistry on 134 estrogen receptor (ER + ) primary breast cancer samples confirmed that high eIF4E expression was significantly associated with increased ERα and FOXM1, and significantly associated with tamoxifen resistance. Our study uncovers a novel mechanism whereby phosphorylation independent eIF4E translational reprogramming in governing the protein synthesis of ERα and FOXM1 contributes to anti-estrogen insensitivity in ER + breast cancer. In eIF4E overexpressing breast cancer, the increased ERα protein expression in turn enhances FOXM1 transcription, which together with its increased translation regulated by eIF4E, contributes to tamoxifen resistance. Coupled with eIF4E translational regulation, our study highlights an important mechanism conferring tamoxifen resistance via both ERα dependent and independent pathways.

show abstract

SpliceArray Profiling of Breast Cancer Reveals a Novel Variant of NCOR2/SMRT That Is Associated with Tamoxifen Resistance and Control of ERα Transcriptional Activity

Cited by 31 publications

References 32 publications

A Splice Variant of NCOR2, BQ323636.1, Confers Chemoresistance in Breast Cancer by Altering the Activity of NRF2

A Splice Variant of NCOR2, BQ323636.1, Confers Chemoresistance in Breast Cancer by Altering the Activity of NRF2

Identification of epigenetic modulators in human breast cancer by integrated analysis of DNA methylation and RNA-Seq data

Phosphorylation independent eIF4E translational reprogramming of selective mRNAs determines tamoxifen resistance in breast cancer

Contact Info

Product

Resources

About