scholarly journals Inhibition of Triple-Negative Breast Cancer Cell Aggressiveness by Cathepsin D Blockage: Role of Annexin A1

2019 ◽  
Vol 20 (6) ◽  
pp. 1337 ◽  
Author(s):  
Mariana Zóia ◽  
Fernanda Azevedo ◽  
Lara Vecchi ◽  
Sara Mota ◽  
Vinícius Rodovalho ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cathepsin D ◽  
Triple Negative ◽  
Functional Results ◽  
Annexin A1 ◽  
Breast Cancers ◽  
Invasion And Migration ◽  
And Migration ◽  
Induced Apoptosis ◽  
In Silico Molecular Docking

Triple-negative breast cancers (TNBCs) are more aggressive than other breast cancer (BC) subtypes and lack effective therapeutic options. Unraveling marker events of TNBCs may provide new directions for development of strategies for targeted TNBC therapy. Herein, we reported that Annexin A1 (AnxA1) and Cathepsin D (CatD) are highly expressed in MDA-MB-231 (TNBC lineage), compared to MCF-10A and MCF-7. Since the proposed concept was that CatD has protumorigenic activity associated with its ability to cleave AnxA1 (generating a 35.5 KDa fragment), we investigated this mechanism more deeply using the inhibitor of CatD, Pepstatin A (PepA). Fourier Transform Infrared (FTIR) spectroscopy demonstrated that PepA inhibits CatD activity by occupying its active site; the OH bond from PepA interacts with a CO bond from carboxylic acids of CatD catalytic aspartate dyad, favoring the deprotonation of Asp33 and consequently inhibiting CatD. Treatment of MDA-MB-231 cells with PepA induced apoptosis and autophagy processes while reducing the proliferation, invasion, and migration. Finally, in silico molecular docking demonstrated that the catalytic inhibition comprises Asp231 protonated and Asp33 deprotonated, proving all functional results obtained. Our findings elucidated critical CatD activity in TNBC cell trough AnxA1 cleavage, indicating the inhibition of CatD as a possible strategy for TNBC treatment.

scholarly journals MicroRNA-455-3p promotes invasion and migration in triple negative breast cancer by targeting tumor suppressor EI24

Oncotarget ◽  
2016 ◽  
Vol 8 (12) ◽  
pp. 19455-19466 ◽  
Author(s):  
Zhishuang Li ◽  
Qingyong Meng ◽  
Aifeng Pan ◽  
Xiaojuan Wu ◽  
Jingjing Cui ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Suppressor ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Invasion And Migration ◽  
And Migration

E2F1 transcriptionally regulates CCNA2 expression to promote triple negative breast cancer tumorigenicity

2021 ◽  
pp. 1-14
Author(s):  
Yongbin Lu ◽  
Fei Su ◽  
Hui Yang ◽  
Yi Xiao ◽  
Xiaobin Zhang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Breast Cancer Subtype ◽  
Tumor Development ◽  
Luciferase Reporter ◽  
Invasion And Migration ◽  
E2f Transcription Factor ◽  
Highly Correlated ◽  
And Migration

BACKGROUND: Triple-negative breast cancer (TNBC) is a highly malignant breast cancer subtype with a poor prognosis. The cell cycle regulator cyclin A2 (CCNA2) plays a role in tumor development. Herein, we explored the role of CCNA2 in TNBC. METHODS: We analyzed CCNA2 expression in 15 pairs of TNBC and adjacent tissues and assessed the relationship between CCNA2 expression using the tissue microarray cohort. Furthermore, we used two TNBC cohort datasets to analyze the correlation between CCNA2 and E2F transcription factor 1 (E2F1) and a luciferase reporter to explore their association. Through rescue experiments, we analyzed the effects of E2F1 knockdown on CCNA2 expression and cellular behavior. RESULTS: We found that CCNA2 expression in TNBC was significantly higher than that in adjacent tissues with similar observations in MDA-MB-231 and MDA-MB-468 cells. E2F1 was highly correlated with CCNA2 as observed through bioinformatics analysis (R= 0.80, P< 0.001) and through TNBC tissue verification analysis (R= 0.53, P< 0.001). We determined that E2F1 binds the +677 position within the CCNA2 promoter. Moreover, CCNA2 overexpression increased cell proliferation, invasion, and migration owing to E2F1 upregulation in TNBC. CONCLUSION: Our data indicate that E2F1 promotes TNBC proliferation and invasion by upregulating CCNA2 expression. E2F1 and CCNA2 are potential candidates that may be targeted for effective TNBC treatment.

scholarly journals Induction of AMPK activation by N,N’-Diarylurea FND-4b decreases growth and increases apoptosis in triple negative and estrogen-receptor positive breast cancers

2018 ◽  
Author(s):  
Jeremy Johnson ◽  
Piotr Rychahou ◽  
Vitaliy M Sviripa ◽  
Heidi L Weiss ◽  
Chunming Liu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Cyclin D1 ◽  
Triple Negative ◽  
Immunoblot Analysis ◽  
Acid Synthesis ◽  
Breast Cancers ◽  
Ampk Activation ◽  
Estrogen Receptor Positive ◽  
Induced Apoptosis

PURPOSE: Triple negative breast cancer (TNBC) is the most lethal and aggressive subtype of breast cancer. AMP-activated protein kinase (AMPK) is a major energy regulator that suppresses tumor growth, and 1-(3-chloro-4-((trifluoromethyl)thio)phenyl)-3-(4-(trifluoromethoxy)phenyl)urea (FND-4b) is a novel AMPK activator that inhibits growth and induces apoptosis in colon cancer. The purpose of this project was to test the effects of FND-4b on AMPK activation, proliferation, and apoptosis in breast cancer with a particular emphasis on TNBC. MATERIALS AND METHODS: (i) Estrogen-receptor positive breast cancer (ER+BC; MCF-7, and T-47D), TNBC (MDA-MB-231 and HCC-1806), and breast cancer stem cells were treated with FND-4b for 24h. Immunoblot analysis assessed AMPK, acetyl-CoA carboxylase (ACC), ribosomal protein S6, cyclin D1, and cleaved PARP. (ii) Sulforhodamine B growth assays were performed after treating ER+BC and TNBC cells with FND-4b for 72h. Proliferation was also assessed by counting cells after 72h of FND-4b treatment. (iii) Cell death ELISA assays were performed after treating ER+BC and TNBC cells with FND-4b for 72h. RESULTS: (i) FND-4b increased AMPK activation with concomitant decreases in ACC activity, phosphorylated S6, and cyclin D1 in all subtypes. (ii) FND-4b decreased proliferation in all cells, while dose-dependent growth decreases were found in ER+BC and TNBC. (iii) Increases in apoptosis were observed in ER+BC and the MDA-MB-231 cell line with FND-4b treatment. CONCLUSIONS: Our findings indicate that FND-4b decreases proliferation for a variety of breast cancers by activating AMPK and has notable effects on TNBC. The growth reductions were mediated through decreases in fatty acid synthesis (ACC), mTOR signaling (S6), and cell cycle flux (cyclin D1). ER+BC cells were more susceptible to FND-4b-induced apoptosis, but MDA-MB-231 cells still underwent apoptosis with higher dose treatment. Further development of FND compounds could result in a novel therapeutic for TNBC.

scholarly journals miR-518a-3p Suppresses Triple-Negative Breast Cancer Invasion and Migration Through Regulation of TMEM2

2020 ◽  
Vol 19 ◽  
pp. 153303382097752
Author(s):  
Lin Gan ◽  
Huachao Yang ◽  
Zhifeng Xiong ◽  
Zailiang Yang ◽  
Ting Wang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Cell Invasion ◽  
Therapeutic Target ◽  
Triple Negative ◽  
Janus Kinase ◽  
Potential Therapeutic Target ◽  
Invasion And Migration ◽  
Over Expression ◽  
And Migration

MicroRNAs (miRNAs) are emerging as critical mediators in tumors, including triple-negative breast cancer (TNBC). The role of miR-518a-3p in TNBC was investigated to identify potential therapeutic target. Data from KM Plotter database ( www.kmplot.com ) showed that high miR-518a-3p expression was significantly associated with overall survival of patients with TNBC ( p = 0.04). The expression of miR-518a-3p was dysregulated in TNBC cells. Functional assays revealed that over-expression of miR-518a-3p inhibited cell invasion and migration of TNBC. Additionally, miR-518a-3p could target TMEM2 (transmembrane protein 2), and decreased protein and mRNA expression of TMEM2 in TNBC cells. Knockdown of TMEM2 suppressed cell invasion and migration through inhibiting phospho (p)-JAK1 (Janus kinase 1) and p-STAT (signal transducer and activator of transcription protein) 1/2. Moreover, over-expression of TMEM2 counteracted the suppressive effect of miR-518a-3p on TNBC invasion and migration through promoting the levels of p-JAK1 and p-STAT1/2. In conclusion, miR-518a-3p negatively regulates the JAK/STAT pathway via targeting TMEM2 and suppresses invasion and migration in TNBC, suggesting that miR-518a-3p may be a potential therapeutic target in TNBC.

scholarly journals The Fluoro-Thiazolylhydrazone Compound TSC-3C Inhibits Triple Negative Breast Cancer (TNBC) Cell Line Activity by Promoting Apoptosis, Regulating the MAPK Pathway and Inducing Mitochondrial Dysfunction

2020 ◽  
Vol 21 (3) ◽  
pp. 1038
Author(s):  
Jiajia Zhang ◽  
Jiajia Dai ◽  
Qingxuan Zheng ◽  
Shuju Guo ◽  
Yanyan Yu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Mitochondrial Dysfunction ◽  
Cancer Progression ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Mapk Pathway ◽  
Invasion And Migration ◽  
Aggressive Cancer ◽  
Tnbc Cell Line ◽  
And Migration

Triple negative breast cancer (TNBC) is the most aggressive cancer in women, and despite improved treatments, it remains a major cause of morbidity and mortality. We and others have demonstrated that different hybrid compounds targeting PARP/MAPK or other pathways to inhibit cancer progression may lead to promising therapeutic results. We introduced fluorine to alter the physical properties of the compounds. TSC-3C was one of the generated compounds. Upon treatment with TSC-3C, MDA-MB-231 cell proliferation, invasion, and migration were inhibited. TSC-3C induced MDA-MB-231 cell mitochondrial dysfunction and apoptosis, which may be caused by reducing the level of phosphorylated p44/42 MAPK (ERK1/2) and increasing the level of p-JNK. The present study may help to elucidate the role of the MAPK pathway in the development of breast cancer and may promote further research on halogenated heterocyclic compounds for the treatment of breast cancer.

Sign in / Sign up

Export Citation Format

Share Document