scholarly journals Transcriptomic Response of Breast Cancer Cells MDA-MB-231 to Docosahexaenoic Acid: Downregulation of Lipid and Cholesterol Metabolism Genes and Upregulation of Genes of the Pro-Apoptotic ER-Stress Pathway

2020 ◽  
Vol 17 (10) ◽  
pp. 3746 ◽  
Author(s):  
Benoît Chénais ◽  
Marine Cornec ◽  
Solenne Dumont ◽  
Justine Marchand ◽  
Vincent Blanckaert
Keyword(s):  
Breast Cancer ◽  
Docosahexaenoic Acid ◽  
Er Stress ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Molecular Mechanisms ◽  
Health Concern ◽  
Migration And Invasion ◽  
Transcriptomic Response ◽  
The Impact

Despite considerable efforts in prevention and therapy, breast cancer remains a major public health concern worldwide. Numerous studies using breast cancer cell lines have shown the antiproliferative and pro-apoptotic effects of docosahexaenoic acid (DHA). Some studies have also demonstrated the inhibitory effect of DHA on the migration and invasion of breast cancer cells, making DHA a potential anti-metastatic agent. Thus, DHA has shown its potential as a chemotherapeutic adjuvant. However, the molecular mechanisms triggering DHA effects remain unclear, and the aim of this study was to provide a transcriptomic basis for further cellular and molecular investigations. Therefore, MDA-MB-231 cells were treated with 100 µM DHA for 12 h or 24 h before RNA-seq analysis. The results show the great impact of DHA-treatment on the transcriptome, especially after 24 h of treatment. The impact of DHA is particularly visible in genes involved in the cholesterol biosynthesis pathway that is strongly downregulated, and the endoplasmic reticulum (ER)-stress response that is, conversely, upregulated. This ER-stress and unfolded protein response could explain the pro-apoptotic effect of DHA. The expression of genes related to migration and invasion (especially SERPINE1, PLAT, and MMP11) is also impacted by DHA. In conclusion, this transcriptomic analysis supports the antiproliferative, pro-apoptotic and anti-invasive effects of DHA, and provides new avenues for understanding its molecular mechanisms.

scholarly journals FOXA1 upregulation promotes enhancer and transcriptional reprogramming in endocrine-resistant breast cancer

2019 ◽  
Vol 116 (52) ◽  
pp. 26823-26834 ◽  
Author(s):  
Xiaoyong Fu ◽  
Resel Pereira ◽  
Carmine De Angelis ◽  
Jamunarani Veeraraghavan ◽  
Sarmistha Nanda ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Molecular Mechanisms ◽  
Endocrine Resistance ◽  
Metastatic Breast ◽  
Migration And Invasion ◽  
Transcriptional Reprogramming ◽  
The Impact

Forkhead box A1 (FOXA1) is a pioneer factor that facilitates chromatin binding and function of lineage-specific and oncogenic transcription factors. Hyperactive FOXA1 signaling due to gene amplification or overexpression has been reported in estrogen receptor-positive (ER+) endocrine-resistant metastatic breast cancer. However, the molecular mechanisms by which FOXA1 up-regulation promotes these processes and the key downstream targets of the FOXA1 oncogenic network remain elusive. Here, we demonstrate that FOXA1 overexpression in ER+breast cancer cells drives genome-wide enhancer reprogramming to activate prometastatic transcriptional programs. Up-regulated FOXA1 employs superenhancers (SEs) to synchronize transcriptional reprogramming in endocrine-resistant breast cancer cells, reflecting an early embryonic development process. We identify the hypoxia-inducible transcription factor hypoxia-inducible factor-2α (HIF-2α) as the top high FOXA1-induced SE target, mediating the impact of high FOXA1 in activating prometastatic gene sets and pathways associated with poor clinical outcome. Using clinical ER+/HER2−metastatic breast cancer datasets, we show that the aberrant FOXA1/HIF-2α transcriptional axis is largely nonconcurrent with theESR1mutations, suggesting different mechanisms of endocrine resistance and treatment strategies. We further demonstrate the selective efficacy of an HIF-2α antagonist, currently in clinical trials for advanced kidney cancer and recurrent glioblastoma, in reducing the clonogenicity, migration, and invasion of endocrine-resistant breast cancer cells expressing high FOXA1. Our study has uncovered high FOXA1-induced enhancer reprogramming and HIF-2α–dependent transcriptional programs as vulnerable targets for treating endocrine-resistant and metastatic breast cancer.

scholarly journals ΕGFR/ERβ-Mediated Cell Morphology and Invasion Capacity Are Associated with Matrix Culture Substrates in Breast Cancer

Cells ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 2256
Author(s):  
Konstantina Kyriakopoulou ◽  
Eirini Riti ◽  
Zoi Piperigkou ◽  
Konstantina Koutroumanou Sarri ◽  
Heba Bassiony ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cell Morphology ◽  
Breast Cancer Cells ◽  
Type I Collagen ◽  
Morphological Characteristics ◽  
Migration And Invasion ◽  
Type I ◽  
Egfr Inhibition ◽  
The Impact

Breast cancer accounts for almost one in four cancer diagnoses in women. Studies in breast cancer patients have identified several molecular markers, indicators of aggressiveness, which help toward more individual therapeutic approaches. In triple-negative breast cancer (TNBC), epidermal growth factor receptor (EGFR) overexpression is associated with increased metastatic potential and worst survival rates. Specifically, abnormal EGFR activation leads to altered matrix metalloproteinases’ (MMPs) expression and, hence, extracellular matrix (ECM) degradation, resulting in induced migration and invasion. The use of matrix substrates for cell culture gives the opportunity to mimic the natural growth conditions of the cells and their microenvironment, as well as cell–cell and cell–matrix interactions. The aim of this study was to evaluate the impact of EGFR inhibition, estrogen receptor beta (ERβ) and different matrix substrates [type I collagen and fibronectin (FN)] on the functional properties, expression of MMPs and cell morphology of ERβ-positive TNBC cells and shERβ ones. Our results highlight EGFR as a crucial regulator of the expression and activity levels of MMPs, while ERβ emerges as a mediator of MMP7 and MT1-MMP expression. In addition, the EGFR/ERβ axis impacts the adhesion and invasion potential of breast cancer cells on collagen type I. Images obtained by scanning electron microscope (SEM) from cultures on the different matrix substrates revealed novel observations regarding various structures of breast cancer cells (filopodia, extravesicles, tunneling nanotubes, etc.). Moreover, the significant contribution of EGFR and ERβ in the morphological characteristics of these cells is also demonstrated, hence highlighting the possibility of dual pharmacological targeting.

scholarly journals Curcumin derivative WZ35 inhibits tumor cell growth via ROS-YAP-JNK signaling pathway in breast cancer

2019 ◽  
Vol 38 (1) ◽  
Author(s):  
Lihua Wang ◽  
Canwei Wang ◽  
Zheying Tao ◽  
Liqian Zhao ◽  
Zheng Zhu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Mitochondrial Dysfunction ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Molecular Mechanisms ◽  
Migration And Invasion ◽  
Ros Generation ◽  
Antitumor Effects ◽  
Jnk Activation

Abstract Background Breast cancer is the most prevalent cancer among women worldwide. WZ35, an analog of curcumin, has been demonstrated to remarkably improve the pharmacokinetic profiles in vivo compared with curcumin. WZ35 exhibits promising antitumor activity in gastric cancer, HCC, colon cancer. However, antitumor effects of WZ35 in breast cancer and its underlying molecular mechanisms remain unclear. Methods CCK8, Flow cytometry and transwell assays were used to measure cell proliferation, cell cycle arrest, apoptosis, cell migration and invasion. We constructed xenograft mouse model and lung metastasis model to assess the antitumor activities of WZ35 in vivo. To explore the underlying molecular mechanisms of WZ35, we performed a series of overexpression and knockdown experiments. The cellular oxygen consumption rates (OCRs) was measured to assess mitochondrial dysfunction. Results We found that treatment of breast cancer cells with WZ35 exerts stronger anti-tumor activities than curcumin both in vitro and in vivo. Mechanistically, our research showed that WZ35 induced reactive oxygen species (ROS) generation and subsequent YAP mediated JNK activation in breast cancer cells. Abrogation of ROS production markedly attenuated WZ35 induced anti-tumor activities as well as YAP and JNK activation. In addition, ROS mediated YAP and JNK activation induced mitochondrial dysfunction in breast cancer cells. Conclusion Our study showed that novel anti-cancer mechanisms of WZ35 in breast cancer cells and ROS-YAP-JNK pathway might be a potential therapeutic target for the treatment of breast cancer patients.

The roles of microRNA-328-3p on proliferation and radiotherapy in breast cancer

2021 ◽  
Author(s):  
Ying Shi ◽  
Pengli Jiang ◽  
Jinqiu Li ◽  
Shengnan Xu ◽  
Bin Liu
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Breast Carcinogenesis ◽  
Aberrant Expression ◽  
Induced Apoptosis ◽  
Cancer Tissues ◽  
The Impact

Abstract Objectives MicroRNAs regulates varieties of molecular pathways and involve in breast carcinogenesis. Here both breast cancer cell lines and human breast cancer tissues were used to investigate the roles of miR-328-3p in breast cancer. Methods The impact of miR-328-3p on proliferation of MDA-MB-231 and T47D cells was determined by MTT assay. transwell migration and matrigel invasion assays were performed to evaluate effects of miR-328-3p on migration and invasion of breast cancer cells. Caspase 3/7 activities were measured to examine the impact of miR-328-3p on radiotherapy-induced apoptosis in breast cancer cells. The possible binding site of miR-328-3p was verified by dual-luciferase reporter assay. Quantitative real-time polymerase chain reaction was performed to detect miR-328-3p expression level in breast cancer tissues. Western blot and immunohistochemical studies were used to examine protein expression in breast cancer cells and breast cancer tissue, respectively. Results miR-328-3p involved growth, migration and invasion in breast cancer cells and was associated with radiotherapy sensitivity. MiR-328-3p enhanced radiation-induced apoptosis in breast cancer cells by regulating BAX and Bcl-2 expression. Meanwhile, aberrant expression of miR-328-3p was associated with altered expression of PTEN and p-AKT in breast cancer cells. Further study showed miR-328-3p bound to 3’-UTR of PTEN. In addition, breast cancer tissues showed higher level of miR-328-3p than normal breast tissue and higher level of miR-328-3p was seen in lower stage in breast cancer. Conclusions miR-328-3p displayed essential functions in breast carcinogenesis and might be used to predict radiotherapy response and prognosis in breast cancer.

scholarly journals Betulinic Acid Suppresses Breast Cancer Metastasis by Targeting GRP78-Mediated Glycolysis and ER Stress Apoptotic Pathway

2019 ◽  
Vol 2019 ◽  
pp. 1-15 ◽  
Author(s):  
Yifeng Zheng ◽  
Pengxi Liu ◽  
Neng Wang ◽  
Shengqi Wang ◽  
Bowen Yang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Er Stress ◽  
Cancer Cells ◽  
Betulinic Acid ◽  
Breast Cancer Cells ◽  
Molecular Mechanisms ◽  
Cancer Metastasis ◽  
Aerobic Glycolysis ◽  
Breast Cancer Metastasis ◽  
Related Proteins

Targeting aberrant metabolism is a promising strategy for inhibiting cancer growth and metastasis. Research is now geared towards investigating the inhibition of glycolysis for anticancer drug development. Betulinic acid (BA) has demonstrated potent anticancer activities in multiple malignancies. However, its regulatory effects on glycolysis and the underlying molecular mechanisms are still unclear. BA inhibited invasion and migration of highly aggressive breast cancer cells. Moreover, BA could suppress aerobic glycolysis of breast cancer cells presenting as a reduction of lactate production, quiescent energy phenotype transition, and downregulation of aerobic glycolysis-related proteins. In this study, glucose-regulated protein 78 (GRP78) was also identified as the molecular target of BA in inhibiting aerobic glycolysis. BA treatment led to GRP78 overexpression, and GRP78 knockdown abrogated the inhibitory effect of BA on glycolysis. Further studies demonstrated that overexpressed GRP78 activated the endoplasmic reticulum (ER) stress sensor PERK. Subsequent phosphorylation of eIF2α led to the inhibition of β-catenin expression, which resulted in the inhibition of c-Myc-mediated glycolysis. Coimmunoprecipitation assay revealed that BA interrupted the binding between GRP78 and PERK, thereby initiating the glycolysis inhibition cascade. Finally, the lung colonization model validated that BA inhibited breast cancer metastasis in vivo, as well as suppressed the expression of aerobic glycolysis-related proteins. In conclusion, our study not only provided a promising drug for aerobic glycolysis inhibition but also revealed that GRP78 is a novel molecular link between glycolytic metabolism and ER stress during tumor metastasis.

scholarly journals Docosahexaenoic acid monoglyceride induces apoptosis and autophagy in breast cancer cells via lipid peroxidation-mediated endoplasmic reticulum stress

2021 ◽  
Author(s):  
Tian-tian Wang ◽  
Yong Yang ◽  
Feng Wang ◽  
Wen-ge Yang ◽  
Jin-jie Zhang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Endoplasmic Reticulum ◽  
Docosahexaenoic Acid ◽  
Growth Inhibition ◽  
Er Stress ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Control Group ◽  
Dependent Manner ◽  
Mcf 7

Abstract Epidemiologic and pre-clinical studies have shown that marine n-3 polyunsaturated fatty acids (n-3 PUFAs) elicit promising chemoprevention against breast cancer. Docosahexaenoic acid monoglyceride (MAG-DHA), a docosahexaenoic acid sn-1-monoacylglyceroldoes not required pancreatic lipase to be absorbed, eliciting a better bioavailability when compared with other formulations such as DHA-free fatty acid, DHA-triglycerol, or DHA-ethyl ester. However, the anti-cancer actions and underlying mechanisms of MAG-DHA on breast cancer remain to be assessed. In this study, MAG-DHA induced significant growth inhibition in MCF-7 and MDA-MB-231 breast cancer cells in a dose-dependent manner. MAG-DHA treatment (80μM) led to 83.8% and 94.3% growth inhibition between MCF-7 and MDA-MB-231 cells, respectively. MAG-DHA-induced growth inhibition was tightly associated with apoptosis, as evidenced by increased active forms of caspase-3, poly (ADP-ribose) polymerase (PARP) and caspase-12. In particular, MAG-DHA-induced apoptosis was triggered by oxidative stress-mediated endoplasmic reticulum (ER) stress, as evidenced by activation of the PERK-eIF2α pathway in ER. MAG-DHA treatment also strongly suppressed the growth of E0771 murine breast cancer xenografts, significant differences of tumor volume were found between MAG-DHA group (0.271 cm3) and control group (0.875cm3) after 15 daily MAG-DHA treatments. The in vitro anti-breast cancer mechanism of MAG-DHA was supported by the in vivo xenograft model. In addition, MAG-DHA-induced ER stress concomitantly triggered autophagy in these cancer cells, and the induction of autophagy suppressed its ability to induce apoptotic cell death. Our data suggested that MAG-DHA as dietary supplement, in combination with autophagy inhibitors may be a useful therapeutic strategy in treating breast cancer.

scholarly journals Sauchinone inhibits the proliferation, migration and invasion of breast cancer cells by suppressing Akt-CREB-MMP13 signaling pathway

2021 ◽  
Author(s):  
Na Hui Kim ◽  
Nam Ji Sung ◽  
Seokwon Shin ◽  
Deok-Seon Ryu ◽  
Hyung-Sun Youn ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Signaling Pathway ◽  
Breast Cancer Cells ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Migration And Invasion ◽  
Targeted Inhibition ◽  
Novel Target

Sauchinone, a lignan isolated from Saururus chinenesis, is known to exhibit anti-inflammatory and anti-oxidant effects. Recently, sauchinone has been reported to inhibit the growth of various cancer cells, but its effects on breast cancer cells remain poorly understood. In this study, we investigated the effects of sauchinone on the growth of breast cancer cells along with the underlying molecular mechanisms. Our results show that sauchinone treatment markedly inhibited the proliferation, migration, and invasion of breast cancer cells. Sauchinone reduced the phosphorylation of Akt, ERK, and CREB increased by transforming growth factor-β. In particular, sauchinone treatment suppressed the expression of matrix metalloproteinase-13 (MMP13) by regulating the Akt-CREB signaling pathway. Sauchinone was less effective in inhibiting cell migration in Mmp13-knockdown cells than in control cells, suggesting that MMP13 may be a novel target for sauchinone. Our study suggests that sauchinone inhibits the growth of breast cancer cells by attenuating the Akt-CREB-MMP13 pathway. In addition, the targeted inhibition of MMP13 by sauchinone represents a promising approach for the treatment of breast cancer.

Silencing of cluster determinant 36 transmitted by gold nanoparticles inhibits the occurrence and progression of breast cancer by down-regulating the peroxisome proliferative activated receptor signaling pathway

2021 ◽  
Vol 11 (5) ◽  
pp. 789-800
Author(s):  
Maohua Wang ◽  
Jian Xie ◽  
Yong Fu ◽  
Yongchun Zhou ◽  
Maohua Wang
Keyword(s):  
Breast Cancer ◽  
Gold Nanoparticles ◽  
Cancer Cells ◽  
Signaling Pathway ◽  
Colony Formation ◽  
Breast Cancer Cells ◽  
Molecular Mechanisms ◽  
Cell Counting ◽  
Migration And Invasion ◽  
Breast Cancer Cell Lines

Breast cancer is the most commonly diagnosed tumor in women worldwide. Although a range of therapeutic strategies have been developed in recent years, the outcome for patients is often poor. The purpose of this study was to explore the molecular mechanisms of the membrane glycoprotein CD36 in breast cancer. Cells from breast cancer cell lines were transfected with gold nanoparticles protected by liposomes, as gene vectors. Cell counting kit 8 assays were performed to determine cell variability, EdU straining assays were used to evaluate cell proliferation, and colony formation assays were performed to detect cell colony ability. The number of cells involved in migration and invasion was counted using Transwell assays. Lymphangiogenesis formation was assessed using lymphangiogenesis formation assay. Xenograft tumor mice were established, to analyze the effects of CD36. Quantitative real-time polymerase chain reaction (qRT-PCR), western blotting, and immunohistochemistry (IHC) were performed to estimate the expression of genes. Silencing of CD36 inhibited cell variability, proliferation, colony formation, lymphangiogenesis, and repressed cell migration and invasion in vitro. Overexpression of PPAR reversed the effects of the silencing of CD36, and the effects of PPAR upregulation were blocked by PPAR inhibitor. In vivo, tumor growth and lymphangiogenesis and PPAR activation were suppressed by the silencing of CD36. Silencing of CD36 also inhibited the variability, proliferation, colony formation, lymphangiogenesis, migration and invasion of breast cancer cells by suppressing PPAR signaling pathway activation. The CD36 gene was transfected with gold nanoparticles which improved the efficiency of gene transfection. The use of gold nanoparticles provides a new way to study the effects of genes on tumor cells.

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