scholarly journals NRF1-Mediated Oncogenic Reprogramming Drives Estrogen-Induced Breast Carcinogenesis

2018 ◽  
Author(s):  
Jayanta Kumar Das ◽  
Quentin Felty ◽  
Robert Poppiti ◽  
Robert M. Jackson ◽  
Deodutta Roy
Keyword(s):  
Breast Cancer ◽  
Transcriptional Activation ◽  
Epithelial Mesenchymal Transition ◽  
Confocal Imaging ◽  
Cancer Tissue ◽  
Causative Role ◽  
Dependent Manner ◽  
Breast Carcinogenesis ◽  
Human Breast Cancer Tissue ◽  
Mesenchymal Transition

Transcription factor activity of the nuclear respiratory factor 1 protein (NRF1) is increased in breast cancer. Whether this gain of NRF1 activity is directly involved in breast cancer remains unknown. Herein, we report a novel oncogenic function of NRF1 supporting its causative role in breast cancer development and progression. The gain of NRF1 and/or treatment with 17β-estradiol (E2) produced heterogeneous breast cancer stem cells (BCSCs) composed of more than ten distinct cell sub-populations. Flow sorting combined with confocal imaging of markers for pluripotency, epithelial mesenchymal transition (EMT), and BCSCs phenotypically confirmed that the sub-populations of BCSCs arise from cell re-programming. Thus, we determined the molecular actions of NRF1 on its target gene CXCR4 because of its known role in the acquisition of BCSCs through EMT. CXCR4 was activated by NRF1 in a redox dependent manner during malignant transformation. NRF1-induced BCSCs were able to form xenograft tumors in vivo, while inhibiting transcription of CXCR4 prevented xenograft tumor growth. Consistent with our observation of NRF1 driven breast tumorigenesis in the experimental model, higher levels of NRF1 protein expression were also found in human breast cancer tissue specimens. This highly novel role of NRF1 in the stochastic acquisition of BCSCs and their progression to a malignant phenotype may open an entirely new research direction targeting NRF1 signaling in invasive breast cancer. Additionally, the discovery of targeting transcriptional activation of CXCR4 to inhibit NRF1-induced oncogenic transformation provides a mechanistic explanation for estrogen-dependent breast carcinogenesis and opens the new avenues for mechanistic therapeutic strategy against breast cancer.

scholarly journals Nuclear Respiratory Factor 1 Acting as an Oncoprotein Drives Estrogen-Induced Breast Carcinogenesis

Cells ◽  
2018 ◽  
Vol 7 (12) ◽  
pp. 234 ◽  
Author(s):  
Jayanta Das ◽  
Quentin Felty ◽  
Robert Poppiti ◽  
Robert Jackson ◽  
Deodutta Roy
Keyword(s):  
Breast Cancer ◽  
Confocal Imaging ◽  
Cancer Tissue ◽  
Causative Role ◽  
Dependent Manner ◽  
Breast Carcinogenesis ◽  
Mesenchymal Transition ◽  
Nuclear Respiratory Factor ◽  
Nuclear Respiratory Factor 1

We have previously shown nuclear respiratory factor 1 (NRF1)-mediated transcriptional programming of mitobiogenesis contributes to estrogen-induced breast cancer through modulating cell cycle progression. In this study, we report a new role of NRF1 that goes beyond that of programming mitobiogenesis. Specifically, we report a novel oncogenic function of NRF1 supporting its causative role in breast cancer development and progression. The gain of NRF1 and/or treatment with 17β-estradiol (E2) produced heterogeneous breast cancer stem cell (BCSC)-like subsets composed of more than 10 distinct cell sub-populations. Flow sorting combined with confocal imaging of markers for pluripotency, epithelial mesenchymal transition (EMT), and BCSCs phenotypically confirmed that the BCSC-like subset arise from cell re-programming. Thus, we determined the molecular actions of NRF1 on its target gene CXCR4 because of its known role in the acquisition of the BCSC-like subset through EMT. CXCR4 was activated by NRF1 in a redox-dependent manner during malignant transformation. An NRF1-induced BCSC-like subset was able to form xenograft tumors in vivo, while inhibiting transcription of CXCR4 prevented xenograft tumor growth. Consistent with our observation of NRF1-driven breast tumorigenesis in the experimental model, higher protein levels of NRF1 were also found in human breast cancer tissue specimens. This highly novel role of NRF1 in the stochastic acquisition of BCSC-like subsets and their progression to a malignant phenotype may open an entirely new research direction targeting NRF1 signaling in invasive breast cancer. Our discovery of targeting transcriptional activation of CXCR4 to inhibit NRF1-induced oncogenic transformation provides a mechanistic explanation for estrogen-dependent breast carcinogenesis and opens new avenues in strategic therapeutics to fight breast cancer.

scholarly journals RNF20 Is Critical for Snail-Mediated E-Cadherin Repression in Human Breast Cancer

2020 ◽  
Vol 10 ◽  
Author(s):  
Danping Wang ◽  
Yifan Wang ◽  
Xuebiao Wu ◽  
Xiangxing Kong ◽  
Jun Li ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Colony Formation ◽  
Human Breast Cancer ◽  
Epithelial Mesenchymal Transition ◽  
Epigenetic Modification ◽  
Dependent Manner ◽  
Human Breast ◽  
Mesenchymal Transition ◽  
E Cadherin

BackgroundE-cadherin, a hallmark of epithelial-mesenchymal transition (EMT), is often repressed due to Snail-mediated epigenetic modification; however, the exact mechanism remains unclear. There is an urgent need to understand the determinants of tumor aggressiveness and identify potential therapeutic targets in breast cancer.Experimental designWe studied the association of RNF20 with Snail and G9a by co-immunoprecipitation. We employed quantitative real-time PCR, ChIP, transwell assay, colony formation assay, and mammosphere assay to dissect the molecular events associated with the repression of E-cadherin in human breast cancer. We used a proteogenomic dataset that contains 105 breast tumor samples to determine the clinical relevance of RNF20 by Kaplan-Meier analyses.ResultsIn this study, we identified that Snail interacted with RNF20, an E3 ubiquitin-protein ligase responsible for monoubiquitination of H2BK120, and G9a, a methyltransferase for H3K9me2. RNF20 expression led to the inhibition of E-cadherin expression in the human breast cancer cells. Mechanically, we showed that RNF20 and H3K9m2 were enriched on the promoter of E-cadherin and knockdown of Snail reduced the enrichment of RNF20, showing a Snail-dependent manner. RNF20 expression enhanced breast cancer cell migration, invasion, tumorsphere and colony formation. Clinically, patients with high RNF20 expression had shorter overall survival.ConclusionRNF20 expression contributes to EMT induction and breast cancer progression through Snail-mediated epigenetic suppression of E-cadherin expression, suggesting the importance of RNF20 in breast cancer.

scholarly journals Notch1 signaling regulates the epithelial–mesenchymal transition and invasion of breast cancer in a Slug-dependent manner

2015 ◽  
Vol 14 (1) ◽  
pp. 28 ◽  
Author(s):  
Shan Shao ◽  
Xiaoai Zhao ◽  
Xiaojin Zhang ◽  
Minna Luo ◽  
Xiaoxiao Zuo ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Epithelial Mesenchymal Transition ◽  
Dependent Manner ◽  
Mesenchymal Transition ◽  
Notch1 Signaling

ZBTB7A promotes migration, invasion and metastasis of human breast cancer cells through NF-κB-induced epithelial–mesenchymal transition in vitro and in vivo

2019 ◽  
Vol 166 (6) ◽  
pp. 485-493 ◽  
Author(s):  
Anyun Mao ◽  
Maojian Chen ◽  
Qinghong Qin ◽  
Zhijie Liang ◽  
Wei Jiang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Epithelial Mesenchymal Transition ◽  
Migration And Invasion ◽  
Cancer Tissue ◽  
Mesenchymal Transition ◽  
Mcf 7

Abstract It has been generally confirmed that zinc finger and BTB domain containing 7A (ZBTB7A) plays an important role in the occurrence and progression of malignant tumours, but the promotion or inhibition effect is related to tumour type. The mechanism between ZBTB7A and breast cancer is not well understood, so further research is needed. In this study, we first investigated the expression of ZBTB7A in tissue samples of clinical breast cancer patients, MDA-MB-231, MCF-7 and MCF-10A cells. Second, we overexpressed the ZBTB7A in MCF-7 cells and silenced the ZBTB7A in MDA-MB-231 cells using lentivirus transfection technology, respectively, and verified the effect of ZBTB7A on migration and invasion of breast cancer cell lines through in vitro cell function experiments, such as wound-healing assay, migration and invasion assay, quantitative real time reverse transcriptase (qRT-PCR) and western blot. Then, the correlation between the above influences, epithelial–mesenchymal transition (EMT) and NF-κB was analysed. Finally, in vivo tumour transplantation model in nude mice was established to verified the effect of ZBTB7A on metastasis of breast cancer MDA-MB-231 cells. In conclusion, ZBTB7A is highly expressed in cancer tissue, breast cancer cell line MDA-MB-231 and MCF-7. Meanwhile, the high expression of ZBTB7A may promote cell migration, invasion and tumour metastasis, which may be related to EMT events by regulating NF-κB.

scholarly journals Calotropis procera Selectively Impaired the 4T1 Breast Cancer Cells Growth by Preferentially Blocking Akt/mTOR Signaling

2021 ◽  
Vol 5 (Supplement_2) ◽  
pp. 278-278
Author(s):  
Ana Carolina Silveira Rabelo ◽  
Maria Angelica Miglino ◽  
Shirley Arbizu ◽  
Susanne Talcott ◽  
Ana Cláudia Carreira ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Migration ◽  
Cell Viability ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Epithelial Mesenchymal Transition ◽  
Calotropis Procera ◽  
Dependent Manner ◽  
Mesenchymal Transition ◽  
4T1 Breast Cancer

Abstract Objectives To investigate the mechanisms underlying the anticancer activity of Calotropis procera crude phenolics extract (CphE). Methods CphE were obtained from leaves homogenized with ethanol (1g:150 mL), followed by filtration and evaporation using a rotary evaporator. Quercetin was used as a positive control since is one of the major flavonoids in C. procera. 4T1 cells were treated with CphE (31–500 µg gallic acid equivalent (GAE)/mL), quercetin (Q) (0.6–3 µg/mL) or DMSO (control) to assess cell viability using resazurin kit and reactive oxygen species (ROS) using the Carboxy-H2DFFDA probe (Sigma-Aldrich, St Louis, MO). Protein and mRNA expression were investigated using standard procedures and cell migration by wound healing assay. Results 4T1 cell viability was inhibited by CphE (within 31–125 µg GAE/mL) and Q (0.6–3 µg/mL) in a dose-dependent manner, with IC50 = 49.6 µg GAE/mL and 1,75 µg/mL, respectively. However, ROS levels were decreased in cells treated with CphE (down to 0.7-fold of control) while Q induced ROS (up to 1.5-fold of control). These results suggest a contrasting response from 4T1 breast cancer cells to individual phenolics present in CphE. The CphE-induced caspase and PARP-dependent apoptosis and cell viability suppression were mediated by CphE-mediated oxidative stress reduction consistent with phospho-ERK1/2 downregulation (down to 0.4-fold of control). Conversely, Q apoptotic and cell viability suppression mechanisms are mediated by induction of ROS-phospho-ERK1/2 (up to 1.6-fold of control) axis. The Akt/mTOR/CREB pathway was downregulated at a similar extend by CphE and Q, consistent with cell migration (suppressed by 40% and 20% by CphE and Q, respectively) and with protein levels of phospho-Src (downregulated to ∼ 0.2-fold and 0.4-fold of control) and phospho-CREB (0.7-fold and 0.6-fold of control) by CphE and Q, respectively. Conclusions CphE inhibited cell viability, induced apoptosis and reduced cell migration. These effects were the result of the modulation of proteins that play an important role in epithelial-mesenchymal transition and cell invasion. These findings provide new insights into the anti-cancer mechanisms of C. procera as a promising herb used in folk medicine for breast cancer treatment. Funding Sources Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES); Universidade de São Paulo (USP).

scholarly journals LncRNA SNHG15 facilitates development of breast cancer (BC) by upregulating c-Myc through sponging miR-451

2020 ◽  
Author(s):  
Jiang Du ◽  
Hong Zhong ◽  
Binlin Ma
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Epithelial Mesenchymal Transition ◽  
Pearson Correlation ◽  
Cell Counting ◽  
Luciferase Reporter ◽  
Blue Staining ◽  
Dependent Manner ◽  
Luciferase Reporter Gene ◽  
Mesenchymal Transition

Abstract Background: Emerging evidences suggested that LncRNA SNHG15 functioned as an oncogene to promote breast cancer (BC) progression, but the detailed mechanisms are still not fully delineated.Methods: The expression levels of the associated genes were examined by using the Real-Time qPCR and Western Blot. Dual-luciferase reporter gene system was performed to validated the potential targeting sites. Cell counting kit-8 and colony formation assay were used to measure cell proliferation, and trypan blue staining and Annexin V-FITC/PI double staining assay were performed to determine cell viability and apoptosis. Cell invasion and migration were examined by transwell and wound scratch assay, respectively. The tumor-bearing mice models were established, and immunohistochemistry (IHC) was conducted to examine expression and localization of Ki67 protein in tumor tissues.Results: Here we identified that LncRNA SNHG15 upregulated c-Myc to facilitate BC progression by sponging miR-451 in a competing endogenous RNA (ceRNA)-dependent manner in vitro and in vivo. Mechanistically, LncRNA SNHG15 and c-Myc were upregulated, while miR-451 was downregulated in BC cells and clinical tissues, compared to their normal counterparts. As expected, the Pearson correlation analysis results indicated that miR-451 negatively correlated with LncRNA SNHG15 and c-Myc, and LncRNA SNHG15 was positively relevant to c-Myc in BC tissues. Next, we validated that LncRNA SNHG15 sponged miR-451 to upregulate c-Myc in BC cells. Further gain- and loss-function experiments evidenced that LncRNA SNHG15 promoted, while miR-451 inhibited malignant phenotypes, including cell proliferation, viability, migration, invasion and epithelial-mesenchymal transition (EMT) in BC cells. Interestingly, the inhibiting effects of LncRNA SNHG15 ablation on BC progression were abrogated by both silencing miR-451 and overexpressing c-Myc.Conclusions: Collectively, the present study evidenced that targeting LncRNA SNHG15/miR-451/c-Myc signaling cascade was novel to hamper BC progression, and the potential underlying mechanisms were also uncovered, which broadened our knowledge in this field, and provided potential biomarkers for BC diagnosis and treatment.

scholarly journals Contribution of miRNAs in the Pathogenesis of Breast Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Soudeh Ghafouri-Fard ◽  
Ali Khanbabapour Sasi ◽  
Atefe Abak ◽  
Hamed Shoorei ◽  
Ali Khoshkar ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Expression Profiling ◽  
Epithelial Mesenchymal Transition ◽  
Breast Carcinogenesis ◽  
Mesenchymal Transition ◽  
Non Invasive ◽  
Heterogeneous Nature ◽  
Almost All ◽  
Resistance To Chemotherapy

Breast cancer is the most frequently diagnosed cancer among females. Gene expression profiling methods have shown the deregulation of several genes in breast cancer samples and have confirmed the heterogeneous nature of breast cancer at the genomic level. microRNAs (miRNAs) are among the recently appreciated contributors in breast carcinogenic processes. These small-sized transcripts have been shown to partake in breast carcinogenesis through modulation of apoptosis, autophagy, and epithelial–mesenchymal transition. Moreover, they can confer resistance to chemotherapy. Based on the contribution of miRNAs in almost all fundamental aspects of breast carcinogenesis, therapeutic intervention with their expression might affect the course of this disorder. Moreover, the presence of miRNAs in the peripheral blood of patients potentiates these transcripts as tools for non-invasive diagnosis of breast cancer.

scholarly journals PGK1 is a Potential Survival Biomarker and Invasion Promoter by Regulating the HIF-1α–Mediated Epithelial-Mesenchymal Transition Process in Breast Cancer

2018 ◽  
Vol 51 (5) ◽  
pp. 2434-2444 ◽  
Author(s):  
Deyuan Fu ◽  
Chunlan He ◽  
Jinli Wei ◽  
Zhengquan Zhang ◽  
Yulin Luo ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Epithelial Mesenchymal Transition ◽  
Target Therapy ◽  
Enzymatic Reaction ◽  
Disease Free Survival ◽  
Transition Process ◽  
Dependent Manner ◽  
Poor Overall Survival ◽  
Mesenchymal Transition

Background/Aims: Glycolysis, a multi-step enzymatic reaction, is considered to be the root of cancer development and progression. The aim of this study is to figure out which glycolysis enzyme participates in the progression of breast cancer and its possible mechanisms. Materials: We firstly screened out PGK1 by performing an RT-PCR array of glycolysis-related genes in three paired breast cancer samples, and further investigated PGK1 using TCGA and our own database. The effect and mechanism of PGK1 on cell invasion was further explored both in vitro and using patient samples. Results: PGK1 was most upregulated in T3N0 with distant metastases compared to those with no metastases. In the TCGA database, high PGK1 expression predicted poor overall survival (OS) in breast cancer and some other cancers (P< 0.001). In the validation cohort, high PGK1 expression was significantly correlated with larger tumor size (P=0.011) and advanced TNM stage (P=0.033), and PGK1 expression was an independent prognostic factor for OS and disease free survival (DFS) in both univariate and multivariate regression analyses (P< 0.05). Functional studies indicated that knockdown of PGK1 expression significantly inhibited invasion and reversed the epithelial-mesenchymal transition process in breast cancer cells (P< 0.05). Mechanistically, PGK1 increased HRE luciferase activity in a dose-dependent manner, while silencing PGK1 expression decreased HRE activity. Conclusion: High PGK1 expression was associated with poor prognosis in breast cancer, because PGK1 and HIF-1α formed a positive feed-forward loop and thus stimulated breast cancer progression and metastases. Based on these results, PGK1 may serve as a promising biomarker and target therapy for breast cancer.

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