scholarly journals RNF208, an estrogen-inducible E3 ligase, targets soluble Vimentin to suppress metastasis in triple-negative breast cancers

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Kyoungwha Pang ◽  
Jinah Park ◽  
Sung Gwe Ahn ◽  
Jihee Lee ◽  
Yuna Park ◽  
...  
Keyword(s):  
Estrogen Receptor Alpha ◽  
Triple Negative ◽  
Ring Finger ◽  
Proteasomal Degradation ◽  
Degradation Pathway ◽  
Tumor Formation ◽  
Negative Regulator ◽  
Soluble Form ◽  
Dependent Manner ◽  
Breast Cancers

AbstractThe development of triple-negative breast cancer (TNBC) negatively impacts both quality of life and survival in a high percentage of patients. Here, we show that RING finger protein 208 (RNF208) decreases the stability of soluble Vimentin protein through a polyubiquitin-mediated proteasomal degradation pathway, thereby suppressing metastasis of TNBC cells. RNF208 was significantly lower in TNBC than the luminal type, and low expression of RNF208 was strongly associated with poor clinical outcomes. Furthermore, RNF208 was induced by 17β-estradiol (E2) treatment in an estrogen receptor alpha (ΕRα)-dependent manner. Overexpression of RNF208 suppresses tumor formation and lung metastasis of TNBC cells. Mechanistically, RNF208 specifically polyubiquitinated the Lys97 residue within the head domain of Vimentin through interaction with the Ser39 residue of phosphorylated Vimentin, which exists as a soluble form, eventually facilitating proteasomal degradation of Vimentin. Collectively, our findings define RNF208 as a negative regulator of soluble Vimentin and a prognostic biomarker for TNBC cells.

scholarly journals CHFR regulates chemoresistance in triple-negative breast cancer through destabilizing ZEB1

2021 ◽  
Vol 12 (9) ◽  
Author(s):  
Hong Luo ◽  
Zhicheng Zhou ◽  
Shan Huang ◽  
Mengru Ma ◽  
Manyu Zhao ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Triple Negative Breast Cancer ◽  
Fatty Acid Synthase ◽  
Triple Negative ◽  
Trichostatin A ◽  
Affinity Purification ◽  
Negative Regulator ◽  
Dependent Manner ◽  
Breast Cancers

AbstractFailures to treat triple-negative breast cancer (TNBC) are mainly due to chemoresistance or radioresistance. We and others previously discovered that zinc finger E-box-binding homeobox 1 (ZEB1) is a massive driver causing these resistance. However, how to dynamically modulate the intrinsic expression of ZEB1 during cell cycle progression is elusive. Here integrated affinity purification combined with mass spectrometry and TCGA analysis identify a cell cycle-related E3 ubiquitin ligase, checkpoint with forkhead and ring finger domains (CHFR), as a key negative regulator of ZEB1 in TNBC. Functional studies reveal that CHFR associates with and decreases ZEB1 expression in a ubiquitinating-dependent manner and that CHFR represses fatty acid synthase (FASN) expression through ZEB1, leading to significant cell death of TNBC under chemotherapy. Intriguingly, a small-molecule inhibitor of HDAC under clinical trial, Trichostatin A (TSA), increases the expression of CHFR independent of histone acetylation, thereby destabilizes ZEB1 and sensitizes the resistant TNBC cells to conventional chemotherapy. In patients with basal-like breast cancers, CHFR levels significantly correlates with survival. These findings suggest the therapeutic potential for targeting CHFR-ZEB1 signaling in resistant malignant breast cancers.

scholarly journals Use of Proton Pump Inhibitors as Adjunct Treatment for Triple-Negative Breast Cancers. An Introductory Study

2014 ◽  
Vol 17 (3) ◽  
pp. 439 ◽  
Author(s):  
Wayne Goh ◽  
Inna Sleptsova-Freidrich ◽  
Nenad Petrovic
Keyword(s):  
Breast Cancer ◽  
Cancer Treatment ◽  
Cancer Cells ◽  
Proton Pump ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Dependent Manner ◽  
Breast Cancers ◽  
Gastric Type ◽  
Dose Dependent

PURPOSE: Triple negative breast cancers (estrogen, progesterone and human epidermal growth factor 2 (HER2) receptor-negative) are among the most aggressive forms of cancers with limited treatment options. Doxorubicin is one of the agents found in many of the current cancer treatment protocols, although its use is limited by dose-dependent cardiotoxicity. This work investigates one of the ways to suppress cancer growth by inhibiting tumor cell ability to remove acid accumulated during its metabolism by proton pump inhibitor esomeprazole (a drug with extensive clinical use) which could serve as an addition to doxorubicin therapy. METHODS: In this work, we have investigated growth suppression of triple-negative breast cancer cells MDA-MB-468 by esomeprazole and doxorubicin by trypan blue exclusion assay. Measurement of acidification of treated cancer cells was performed using intracellular pH-sensitive probe, BCECF-AM. Finally, expression of gastric type proton pump (H+/K+ ATPase, a target for esomeprazole) on MDA-MB-468 cells was detected by immunofluorescence and Western blotting. RESULTS: We have found that esomeprazole suppresses growth of triple-negative breast cancer cell in vitro in a dose-dependent manner through increase in their intracellular acidification. In contrast, esomeprazole did not have significant effect on non-cancerous breast epithelial MCF-10A cells. Esomeprazole increases doxorubicin effects suggesting that dual treatments might be possible. In addition, response of MDA-MB-468 cells to esomeprazole could be mediated by gastric type proton pump (H+/K+ ATPase) in cancer cells contrary to previous beliefs that this proton pump expression is restricted to parietal cells of the stomach epithelia. CONCLUSION: This study provides first evidence that adjunct use of esomeprazole in breast cancer treatment might be a possible to combat adverse effects of doxorubicin and increase its effectiveness. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

scholarly journals Triterpenoid Saponin AG8 from Ardisia gigantifolia stapf. Induces Triple Negative Breast Cancer Cells Apoptosis through Oxidative Stress Pathway

2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
Li-Hua Mu ◽  
Li-Hua Wang ◽  
Teng-Fei Yu ◽  
Yu-Ning Wang ◽  
Hong Yan ◽  
...  
Keyword(s):  
Triple Negative ◽  
Growth Factor Receptor ◽  
Cell Types ◽  
Ros Generation ◽  
Triterpenoid Saponin ◽  
Dependent Manner ◽  
Breast Cancers ◽  
Underlying Mechanisms ◽  
Apoptotic Pathways ◽  
Dose Dependent

Triple-negative breast cancers (TNBCs) are associated with poor patient survival because of the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expressions. Our previous studies have shown that the triterpenoid saponin AG8 from Ardisia gigantifolia stapf. inhibits the proliferation of MDA-MB-231 cells. In this study, the effects of AG8 were further analyzed in different TNBC cell types: MDA-MB-231, BT-549, and MDA-MB-157 cells. AG8 inhibited the viability of MDA-MB-231, BT-549, and MDA-MB-157 cells in a dose-dependent manner and showed stronger cytotoxicity to African American (AA) and mesenchymal (M) subtypes than Caucasian (CA) and mesenchymal stem-like (MSL) subtypes, respectively. AG8 impaired the uptake of MitoTracker Red CMXRos by the mitochondria of TNBC cells in a dose-dependent manner, and this was recovered by N-acetyl-l-cysteine (NAC). AG8 affected GSH, SOD, and MDA levels of TNBC cells, but different TNBC subtypes had different sensitivities to AG8 and NAC. In addition, we found that AG8 increased the Bax/Bcl-2 ratio and the levels of cytoplasmic cytochrome c and significantly decreased phosphorylation of ERK and AKT in BT549 and MDA-MB-157 cells. AG8 elicited its anticancer effects through ROS generation, ERK and AKT activation, and by triggering mitochondrial apoptotic pathways in TNBC cells. AG8 had selective cytotoxic effects against the AA and M TNBC subtypes and markedly induced MDA-MB-157 (AA subtype) cell apoptosis through pathways that were not associated with ROS, which was different from the other two subtypes. The underlying mechanisms should be further investigated.

scholarly journals Adipsin-Dependent Secretion of Hepatocyte Growth Factor Regulates the Adipocyte-Cancer Stem Cell Interaction

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 4238
Author(s):  
Masahiro Mizuno ◽  
Behnoush Khaledian ◽  
Masao Maeda ◽  
Takanori Hayashi ◽  
Seiya Mizuno ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Adipose Tissue ◽  
Stem Cell ◽  
Growth Factor ◽  
Cancer Stem Cell ◽  
Hepatocyte Growth Factor ◽  
Tumor Formation ◽  
Dependent Manner ◽  
Breast Cancers ◽  
Hepatocyte Growth

Adipose tissue is a component of the tumor microenvironment and is involved in tumor progression. We have previously shown that adipokine adipsin (CFD) functions as an enhancer of tumor proliferation and cancer stem cell (CSC) properties in breast cancers. We established the Cfd-knockout (KO) mice and the mammary adipose tissue-derived stem cells (mADSCs) from them. Cfd-KO in mADSCs significantly reduced their ability to enhance tumorsphere formation of breast cancer patient-derived xenograft (PDX) cells, which was restored by the addition of Cfd in the culture medium. Hepatocyte growth factor (HGF) was expressed and secreted from mADSCs in a Cfd-dependent manner. HGF rescued the reduced ability of Cfd-KO mADSCs to promote tumorsphere formation in vitro and tumor formation in vivo by breast cancer PDX cells. These results suggest that HGF is a downstream effector of Cfd in mADSCs that enhances the CSC properties in breast cancers.

scholarly journals Palmatine Modulates Triple Negative Mammary Carcinoma by Regulating the Endogenous Function of p53, p21 and Mdm2

2021 ◽  
Vol 14 (02) ◽  
pp. 943-954
Author(s):  
Selase Ativui ◽  
Cynthia A. Danquah ◽  
Newman Osafo ◽  
Sammy Ka-Chungu
Keyword(s):  
Breast Cancer ◽  
Mammary Carcinoma ◽  
Tumor Volume ◽  
Triple Negative ◽  
Kinase Inhibitor ◽  
Breast Diseases ◽  
Dependent Manner ◽  
Breast Cancers ◽  
Bioactive Constituents ◽  
Tumor Weight

Natural products and their bioactive constituents have been investigated for centuries and recognized as a source of valuable therapeutic candidates in the development of contemporary anticancer drugs. Triple negative breast cancers are a sub type of malignant cells formed in the breast tissue caused by uncontrolled and abnormal division. Palmatine, a naturally occurring alkaloid extracted from several medicinal plants in West Africa,has not been extensively investigated for its anti-breast cancer properties especially in triple-negative mammary carcinoma. The 4T1 triple-negative breast cancer cells were transplanted orthotopically into the mammary fat pad of the female balb/c mice. Tumor volume,tumor weight, histology and immunohistochemical analysis were carried out.After 28 days, palmatine (1, 5 and 10 mg/kg) in a dose-dependent manner decreased tumor volume (190.80 ±19.14, 25.40 ± 2.82, 14.20 ± 1.85), reduced tumor weight (1.035± 0.04, 0.8027± 0.01, 0.5090±0.04), inhibited tumor growth (31%, 46%, 66%) and protected against morphological dysplasia induced by the carcinoma (3.50 ± 0.29, 2.25 ± 0.25, 1.75 ± 0.25)respectively. Also, palmatine increased the activity of the tumor protein p53, cyclin-dependent kinase inhibitor 1 (p21) and mouse double minute 2(Mdm2) compared to the untreated carcinoma bearingmice. Overall, palmatine protected against triple negative mammary carcinoma and can be a valuable anticancer compound to treat breast diseases.

scholarly journals 2-Methoxy-7-Acetonyljuglone Isolated from Reynoutria japonica Increases the Activity of Nuclear Factor Erythroid 2-Related Factor-2 through Inhibition of Ubiquitin Degradation in HeLa Cells

Antioxidants ◽  
2019 ◽  
Vol 8 (9) ◽  
pp. 398 ◽  
Author(s):  
Jung-Hwan Kim ◽  
Atif Ali Khan Khalil ◽  
Hye-Jin Kim ◽  
Sung-Eun Kim ◽  
Mi-Jeong Ahn
Keyword(s):  
Hela Cells ◽  
Target Genes ◽  
Proteasomal Degradation ◽  
Degradation Pathway ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Dependent Manner ◽  
Nuclear Factor ◽  
Signaling Mechanism ◽  
Reynoutria Japonica

The nuclear factor erythroid-derived 2-related factor 2 (NRF2) is a key transcription factor for the activation of genes responsible for oxidative stress and drug detoxification. Thus, it is important to identify NRF2 activators, which can be used to protect the cells from oxidative damage. Here, we investigated the effect of juglone derivatives isolated from Reynoutria japonica on the activity of NRF2 in HeLa cells. We demonstrated that among the juglone derivatives, 2-methoxy-7-acetonyljuglone (MA) strongly stimulated the antioxidant response element (ARE)-luciferase activity in a dose-dependent manner. In addition, MA significantly increased the nuclear localization of NRF2 and, consequently, increased the expression of NRF2 target genes, including heme oxygenase-1(HO-1), NAD(P)H: quinine oxidoreductase-1 (NQO-1), and glutamate-cysteine ligase catalytic (GCLC). To gain insights into the NRF2 signaling mechanism by MA, we measured the activities of RAC-alpha serine/threonine-protein kinase (AKT) and mitogen-activated protein (MAP) kinase family proteins, including extracellular signal-regulated kinase (ERK) and p38. Our results showed that MA induced NRF2 activity through p38 and AKT signaling. Subsequently, we found that MA significantly enhanced NRF2 stability by inhibiting ubiquitin-dependent proteasomal degradation. Thus, MA might protect cells by enhancing the activity and stability of NRF2 through inhibition of the proteasomal degradation pathway.

scholarly journals Cytotoxicity of Selenium Immunoconjugates against Triple Negative Breast Cancer Cells

2018 ◽  
Vol 19 (11) ◽  
pp. 3352 ◽  
Author(s):  
Soni Khandelwal ◽  
Mallory Boylan ◽  
Julian Spallholz ◽  
Lauren Gollahon
Keyword(s):  
Breast Cancer ◽  
Side Effects ◽  
Cell Growth ◽  
Cell Lines ◽  
Cancer Cell ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Dependent Manner ◽  
Breast Cancers ◽  
Cancer Cell Growth

Within the subtypes of breast cancer, those identified as triple negative for expression of estrogen receptor α (ESR1), progesterone receptor (PR) and human epidermal growth factor 2 (HER2), account for 10–20% of breast cancers, yet result in 30% of global breast cancer-associated deaths. Thus, it is critical to develop more targeted and efficacious therapies that also demonstrate less side effects. Selenium, an essential dietary supplement, is incorporated as selenocysteine (Sec) in vivo into human selenoproteins, some of which exist as anti-oxidant enzymes and are of importance to human health. Studies have also shown that selenium compounds hinder cancer cell growth and induce apoptosis in cancer cell culture models. The focus of this study was to investigate whether selenium-antibody conjugates could be effective against triple negative breast cancer cell lines using clinically relevant, antibody therapies targeted for high expressing breast cancers and whether selenium cytotoxicity was attenuated in normal breast epithelial cells. To that end, the humanized monoclonal IgG1 antibodies, Bevacizumab and Trastuzumab were conjugated with redox selenium to form Selenobevacizumab and Selenotrastuzumab and tested against the triple negative breast cancer (TNBC) cell lines MDA-MB-468 and MDA-MB-231 as well as a normal, immortalized, human mammary epithelial cell line, HME50-5E. VEGF and HER2 protein expression were assessed by Western. Although expression levels of HER2 were low or absent in all test cells, our results showed that Selenobevacizumab and Selenotrastuzumab produced superoxide (O2•−) anions in the presence of glutathione (GSH) and this was confirmed by a dihydroethidium (DHE) assay. Interestingly, superoxide was not elevated within HME50-5E cells assessed by DHE. The cytotoxicity of selenite and the selenium immunoconjugates towards triple negative cells compared to HME-50E cells was performed in a time and dose-dependent manner as measured by Trypan Blue exclusion, MTT assay and Annexin V assays. Selenobevacizumab and Selenotrastuzumab were shown to arrest the cancer cell growth but not the HME50-5E cells. These results suggest that selenium-induced toxicity may be effective in treating TNBC cells by exploiting different immunotherapeutic approaches potentially reducing the debilitating side effects associated with current TNBC anticancer drugs. Thus, clinically relevant, targeting antibody therapies may be repurposed for TNBC treatment by attachment of redox selenium.

scholarly journals Dual Target of EGFR and mTOR Suppress Triple Negative Breast Cancer Cell Growth Via Regulation The Phosphorylation of mTOR Downstream Proteins

2021 ◽  
Author(s):  
Jing Ma ◽  
Hongtao Li ◽  
Yanzhen Cao ◽  
Jingjing Fan ◽  
Binlin Ma
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Cell Model ◽  
Mammalian Target Of Rapamycin ◽  
Alternative Activation ◽  
Dependent Manner ◽  
Breast Cancers ◽  
Breast Cancer Cell Growth ◽  
Mtor Protein

Abstract Background：Triple-negative breast cancers (TNBC) are the most aggressive subtype of breast cancer, accounting for 15% - 20% of all cases, and have no response to available hormonal therapies and anti-HER2-targeted therapies due to the absence of corresponding targets. Over half of TNBC patients have overexpressed EGFR, but they are insensitive to EGFR inhibitors from monotherapy. Mammalian target of rapamycin (mTOR) connected with EGFR in the downstream signaling and involved in the progress of TNBC. The purpose of this study is to determine the combined effect of everolimus and geftinib in a TNBC cell model and investigate the possible mechanism. Results: This work showed the expression EGFR and p-mTOR protein in TNBC tissues were significantly higher than that in non-TNBC(p<0.05), while the expression of mTOR, S6K1, pEGFR and p-S6K1 were significantly higher in the EGF stimulation. EGFR and p-mTOR protein are related to poor prognosis. EGFR inhibitor gefitinib and mTOR inhibitor everolimus significantly inhibited the proliferation of human triple-negative breast cancer MDA-MB-468 cells and arrested cells in G0/G1 phase when applied separately and in combination in a dose-dependent manner (P<0.05). Meanwhile, the rate of apoptosis of MDA-MB-468 cells was significantly incresased separately by two drugs (P<0.01). Furthermore, the combination of everolimus and geftinib reduced the phosphorylation of mTOR downstream proteins. Instead, the phosphorylation of 4E-BP1 was enhanced after the everolimus and geftinib treatment, indicated an alternative activation pattern. Conclusions: These results suggested that dual inhibition of mTOR and EGFR could be a promising approach to treat TNBC.

scholarly journals Metabolically activated adipose tissue macrophages link obesity to triple-negative breast cancer

2019 ◽  
Vol 216 (6) ◽  
pp. 1345-1358 ◽  
Author(s):  
Payal Tiwari ◽  
Ariane Blank ◽  
Chang Cui ◽  
Kelly Q. Schoenfelt ◽  
Guolin Zhou ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Adipose Tissue ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Tumor Formation ◽  
Dependent Manner ◽  
Macrophage Phenotype ◽  
M1 Macrophages ◽  
Adipose Tissue Macrophages ◽  
Macrophage Accumulation

Obesity is associated with increased incidence and severity of triple-negative breast cancer (TNBC); however, mechanisms underlying this relationship are incompletely understood. Here, we show that obesity reprograms mammary adipose tissue macrophages to a pro-inflammatory metabolically activated phenotype (MMe) that alters the niche to support tumor formation. Unlike pro-inflammatory M1 macrophages that antagonize tumorigenesis, MMe macrophages are pro-tumorigenic and represent the dominant macrophage phenotype in mammary adipose tissue of obese humans and mice. MMe macrophages release IL-6 in an NADPH oxidase 2 (NOX2)–dependent manner, which signals through glycoprotein 130 (GP130) on TNBC cells to promote stem-like properties including tumor formation. Deleting Nox2 in myeloid cells or depleting GP130 in TNBC cells attenuates obesity-augmented TNBC stemness. Moreover, weight loss reverses the effects of obesity on MMe macrophage inflammation and TNBC tumor formation. Our studies implicate MMe macrophage accumulation in mammary adipose tissue as a mechanism for promoting TNBC stemness and tumorigenesis during obesity.

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