scholarly journals The orphan nuclear receptor estrogen-related receptor beta (ERRβ) in triple-negative breast cancer

2019 ◽  
Author(s):  
Aileen I. Fernandez ◽  
Xue Geng ◽  
Krysta Chaldekas ◽  
Brent Harris ◽  
Anju Duttargi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Transcription Factor ◽  
Mrna Expression ◽  
Cell Lines ◽  
Copy Number ◽  
Orphan Nuclear Receptor ◽  
Transcription Factor Activity ◽  
Factor Activity ◽  
Tnbc Cell ◽  
Estrogen Related Receptor

ABSTRACTPurposeTriple negative breast cancer (TNBC)/ basal-like breast cancer (BLBC) is a highly aggressive form of breast cancer prevalent in African-American (AA) women. We previously reported that a small molecule agonist ligand for the orphan nuclear receptor estrogen-related receptor beta (ERRβ or ESRRB) has growth inhibitory and anti-mitotic activity in TNBC cell lines. In this study, we evaluate the association of ESRRB mRNA, copy number levels, and protein expression with demographic, clinicopathological, and gene expression features in breast tumor clinical specimens.MethodsESRRB mRNA level expression and clinical associations were analyzed using RNAseq data. Array-based comparative genomic hybridization determined ESRRB copy number in AA and Caucasian women. Transcription factor activity was measured using promoter-reporter luciferase assays in TNBC cell lines. Semi-automatic quantification of immunohistochemistry measured ERRβ protein expression on a 150-patient tissue microarray series.ResultsESRRB mRNA expression is significantly lower in TNBC/BLBC vs. other breast cancer subtypes. There is no evidence of ESRRB copy number loss. ESRRB mRNA expression is correlated with the expression of genes associated with neuroactive ligand-receptor interaction, metabolic pathways, and deafness. These genes contain G/C-rich transcription factor binding motifs. The ESRRB message is alternatively spliced into three isoforms, which we show have different transcription factor activity in basal-like vs. other TNBC cell lines. We further show that the ERRβ2 and ERRβsf isoforms are broadly expressed in breast tumors at the protein level.ConclusionsDecreased ESRRB mRNA expression, and distinct patterns of ERRβ isoform subcellular localization and transcription factor activity are key features in TNBC/BLBC.

scholarly journals Orphan Nuclear Receptor Nur77 Is Involved in Caspase-independent Macrophage Cell Death

2003 ◽  
Vol 197 (11) ◽  
pp. 1441-1452 ◽  
Author(s):  
Sung Ouk Kim ◽  
Koh Ono ◽  
Peter S. Tobias ◽  
Jiahuai Han
Keyword(s):  
Cell Death ◽  
Transcription Factor ◽  
Orphan Nuclear Receptor ◽  
Transcription Factor Activity ◽  
Factor Activity ◽  
Septic Mouse ◽  
Tlr4 Signaling ◽  
Activation Induced Cell Death ◽  
Extracellular Signal ◽  
Reporter Gene Analysis

Activation-induced cell death in macrophages has been observed, but the mechanism remains largely unknown. Activation-induced cell death in macrophages can be independent from caspases, and the death of activated macrophages can even be triggered by the pan-caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone (zVAD). Here, we show that this type of macrophage death can occur in the septic mouse model and that toll-like receptor (TLR)-2 or TLR4 signaling is required in this process. We conclude that Nur77 is involved in the macrophage death because Nur77 expression correlates with cell death, and cell death is reduced significantly in Nur77-deficient macrophages. The extracellular signal–regulated kinase pathway, which is downstream of TLR2 or TLR4, and myocyte-specific enhancer binding factor 2 (MEF2) transcription factor activity, which is up-regulated by zVAD, are required for Nur77 induction and macrophage death. Reporter gene analysis suggests that Nap, Ets, Rce, and Sp1 sites in the Nur77 promoter are regulated by TLR4 signaling and that MEF2 sites in the Nur77 promoter are regulated by zVAD treatment. MEF2 transcription factors are constitutively expressed and degraded in macrophages, and zVAD increases MEF2 transcription factor activity by preventing the proteolytic cleavage and degradation of MEF2 proteins. This paper delineates the dual signaling pathways that are required for Nur77 induction in macrophages and demonstrates a role of Nur77 in caspase-independent cell death.

scholarly journals Identification of Post-Transcriptional Modulators of Breast Cancer Transcription Factor Activity Using MINDy

PLoS ONE ◽  
2016 ◽  
Vol 11 (12) ◽  
pp. e0168770 ◽  
Author(s):  
Thomas M. Campbell ◽  
Mauro A. A. Castro ◽  
Bruce A. J. Ponder ◽  
Kerstin B. Meyer
Keyword(s):  
Breast Cancer ◽  
Transcription Factor ◽  
Transcription Factor Activity ◽  
Factor Activity ◽  
Transcriptional Modulators

Bond oracle HER2 IHC assay for identifying low to intermediate HER2-expressing breast cancer.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e11509-e11509
Author(s):  
Victoria Ann Reid ◽  
Mark W. Schwartz ◽  
Sonia Kumar ◽  
Yvonne Alexandra White ◽  
Rosemary Mazanet
Keyword(s):  
Breast Cancer ◽  
Mrna Expression ◽  
Cell Lines ◽  
Breast Cancer Cell ◽  
Copy Number ◽  
Breast Tumors ◽  
Breast Cancer Cell Lines ◽  
Her2 Expression ◽  
Her2 Receptor ◽  
Her2 Protein

e11509 Background: HER2 targeted therapies are effective treatment for breast tumors that overexpress the HER2 protein to a high level (IHC score of 3+) or have amplification of the HER2 gene (HER2/CEP17 >2). However, the majority of breast tumors exhibit low to intermediate expression of HER2 (IHC 1+ and 2+), for which there are limited treatment options. A new cancer vaccine candidate, E75 or nelipepimut-S, offers prevention of reoccurrence in these patients by generating a specific immune response to a HER2 peptide. To date, no companion diagnostic test is validated to differentiate HER2 at these levels of expression. The BOND Oracle HER2 IHC assay (Leica Biosystems) is being validated to reliably identify IHC HER2 1+ and 2+ cases by correlating to independent analytical measures of HER2 expression. Methods: Quantitative PCR was used to determine HER2 DNA copy number and mRNA expression in eight breast cancer cell lines spanning HER2 IHC scores of 0 to 3+ and 45 formalin fixed, paraffin embedded (FFPE) invasive breast tumor samples. HER2 receptor load was determined for the eight cell lines by flow cytometry. Data was correlated to HER2 expression levels as determined by manual interpretation using the BOND Oracle HER2 IHC assay. Results: Previous testing by Leica Biosystems (Table) demonstrates the relationship between HER2 receptor load, HER2 copy number, and HER2 IHC status on four assay control breast cancer cell lines. Preliminary results also show that HER2 mRNA expression correlates with IHC staining with the BOND Oracle HER2 IHC Assay in FFPE breast cancer tissue samples. Conclusions: Improving the discrimination of HER2 protein expression (IHC 1+, 2+) using the Bond Oracle HER2 IHC assay in breast cancer tumors will identify patients for new treatments in development such as E75. [Table: see text]

scholarly journals Overexpression of SERPINA3 promotes tumor invasion and migration, epithelial-mesenchymal-transition in triple-negative breast cancer cells

Breast Cancer ◽  
2021 ◽  
Author(s):  
Yingzi Zhang ◽  
Jiao Tian ◽  
Chi Qu ◽  
Yang Peng ◽  
Jinwei Lei ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Cell Lines ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Epithelial Mesenchymal Transition ◽  
Cell Counting ◽  
Migration And Invasion ◽  
Mesenchymal Transition ◽  
Tnbc Cell

Abstract Background Recent studies have indicated that serpin peptidase inhibitor, clade A, member 3 (SERPINA3) is a potential marker associated with tumor progression, which connoted that SERPINA3 is related to malignant phenotypes in cancer. However, the biological function of SERPINA3 in breast cancer (BC) remains unclear. Methods Bioinformatics data were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Immunohistochemical staining (IHC) was conducted to determine SERPINA3 expression. With strong aggressive abilities, triple-negative breast cancer (TNBC) cell lines (MDA-MB-231, BT549 and MDA-MB-436) were obtained to examine SERPINA3 expression and functions. Wound healing and Transwell assays were performed to measure cell migration and invasion. Cell Counting Kit-8 (CCK-8) assay was conducted to detect cell proliferation abilities and cell viabilities. Results SERPINA3 was upregulated in BC tissues. Functional assays suggested that overexpression of SERPINA3 significantly promoted cell proliferation, where migration and invasion of TNBC cells were accelerated. Knockdown of SERPINA3 had the opposite effects. These results causing by overexpression of SERPINA3 were also confirmed in non-TNBC cell lines. Overexpression of SERPINA3 remarkably enhanced the epithelial–mesenchymal transition (EMT) by upregulating the EMT markers and EZH2. In addition, the overexpression of SERPINA3 reduced the sensitivity of TNBC cells to cisplatin. Conclusion SERPINA3 can regulate the migration, invasion and EMT of TNBC cells and increased expression of SERPINA3 confers resistance to cisplatin in TNBC cells. We discern it is required for the regulation of BC progression and is a critical target for the clinical treatment of BC.

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