scholarly journals CircNR3C2 promotes HRD1-mediated tumor-suppressive effect via sponging miR-513a-3p in triple-negative breast cancer

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Ya Fan ◽  
Jia Wang ◽  
Wen Jin ◽  
Yifei Sun ◽  
Yuemei Xu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Rna Sequencing ◽  
Cancer Progression ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Proteasomal Degradation ◽  
Circular Rnas ◽  
Mesenchymal Transition

Abstract Background E3 ubiquitin ligase HRD1 (HMG-CoA reductase degradation protein 1, alias synoviolin with SYVN1 as the official gene symbol) was found downregulated and acting as a tumor suppressor in breast cancer, while the exact expression profile of HRD1 in different breast cancer subtypes remains unknown. Recent studies characterized circular RNAs (circRNAs) playing an regulatory role as miRNA sponge in tumor progression, presenting a new viewpoint for the post-transcriptional regulation of cancer-related genes. Methods Examination of the expression of HRD1 protein and mRNA was implemented using public microarray/RNA-sequencing datasets and breast cancer tissues/cell lines. Based on public RNA-sequencing results, online databases and enrichment/clustering analyses were used to predict the specific combinations of circRNA/miRNA that potentially govern HRD1 expression. Gain-of-function and rescue experiments in vitro and in vivo were executed to evaluate the suppressive effects of circNR3C2 on breast cancer progression through HRD1-mediated proteasomal degradation of Vimentin, which was identified using immunoblotting, immunoprecipitation, and in vitro ubiquitination assays. Results HRD1 is significantly underexpressed in triple-negative breast cancer (TNBC) against other subtypes and has an inverse correlation with Vimentin, inhibiting the proliferation, migration, invasion and EMT (epithelial-mesenchymal transition) process of breast cancer cells via inducing polyubiquitination-mediated proteasomal degradation of Vimentin. CircNR3C2 (hsa_circ_0071127) is also remarkably downregulated in TNBC, negatively correlated with the distant metastasis and lethality of invasive breast carcinoma. Overexpressing circNR3C2 in vitro and in vivo leads to a crucial enhancement of the tumor-suppressive effects of HRD1 through sponging miR-513a-3p. Conclusions Collectively, we elucidated a bona fide circNR3C2/miR-513a-3p/HRD1/Vimentin axis that negatively regulates the metastasis of TNBC, suggesting that circNR3C2 and HRD1 can act as potential prognostic biomarkers. Our study may facilitate the development of therapeutic agents targeting circNR3C2 and HRD1 for patients with aggressive breast cancer.

scholarly journals CircWAC induces chemotherapeutic resistance in triple-negative breast cancer by targeting miR-142, upregulating WWP1 and activating the PI3K/AKT pathway

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Lei Wang ◽  
Yehui Zhou ◽  
Liang Jiang ◽  
Linlin Lu ◽  
Tiantian Dai ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Luciferase Reporter ◽  
Akt Pathway ◽  
Circular Rnas ◽  
Chemotherapeutic Resistance ◽  
Repressive Effect

Abstract Background Chemotherapeutic resistance is the main cause of clinical treatment failure and poor prognosis in triple-negative breast cancer (TNBC). There is no research on chemotherapeutic resistance in TNBC from the perspective of circular RNAs (circRNAs). Methods TNBC-related circRNAs were identified based on the GSE101124 dataset. Quantitative reverse transcription PCR was used to detect the expression level of circWAC in TNBC cells and tissues. Then, in vitro and in vivo functional experiments were performed to evaluate the effects of circWAC in TNBC. Results CircWAC was highly expressed in TNBC and was associated with worse TNBC patient prognosis. Subsequently, it was verified that downregulation of circWAC can increase the sensitivity of TNBC cells to paclitaxel (PTX) in vitro and in vivo. The expression of miR-142 was negatively correlated with circWAC in TNBC. The interaction between circWAC and miR-142 in TNBC cells was confirmed by RNA immunoprecipitation assays, luciferase reporter assays, pulldown assays, and fluorescence in situ hybridization. Mechanistically, circWAC acted as a miR-142 sponge to relieve the repressive effect of miR-142 on its target WWP1. In addition, the overall survival of TNBC patients with high expression of miR-142 was significantly better than that of patients with low expression of miR-142, and these results were verified in public databases. MiR-142 regulated the expression of WWP1 and the activity of the PI3K/AKT pathway. It was confirmed that WWP1 is highly expressed in TNBC and that the prognosis of patients with high WWP1 expression is poor. Conclusions CircWAC/miR-142/WWP1 form a competing endogenous RNA (ceRNA) network to regulate PI3K/AKT signaling activity in TNBC cells and affect the chemosensitivity of cells.

scholarly journals CD73 facilitates EMT progression and promotes lung metastases in triple-negative breast cancer

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Nataliia Petruk ◽  
Sanni Tuominen ◽  
Malin Åkerfelt ◽  
Jesse Mattsson ◽  
Jouko Sandholm ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Epithelial Mesenchymal Transition ◽  
Lung Metastases ◽  
Vimentin Expression ◽  
Mesenchymal Transition ◽  
Cell Protrusion

AbstractCD73 is a cell surface ecto-5′-nucleotidase, which converts extracellular adenosine monophosphate to adenosine. High tumor CD73 expression is associated with poor outcome among triple-negative breast cancer (TNBC) patients. Here we investigated the mechanisms by which CD73 might contribute to TNBC progression. This was done by inhibiting CD73 with adenosine 5′-(α, β-methylene) diphosphate (APCP) in MDA-MB-231 or 4T1 TNBC cells or through shRNA-silencing (sh-CD73). Effects of such inhibition on cell behavior was then studied in normoxia and hypoxia in vitro and in an orthotopic mouse model in vivo. CD73 inhibition, through shRNA or APCP significantly decreased cellular viability and migration in normoxia. Inhibition of CD73 also resulted in suppression of hypoxia-induced increase in viability and prevented cell protrusion elongation in both normoxia and hypoxia in cancer cells. Sh-CD73 4T1 cells formed significantly smaller and less invasive 3D organoids in vitro, and significantly smaller orthotopic tumors and less lung metastases than control shRNA cells in vivo. CD73 suppression increased E-cadherin and decreased vimentin expression in vitro and in vivo, proposing maintenance of a more epithelial phenotype. In conclusion, our results suggest that CD73 may promote early steps of tumor progression, possibly through facilitating epithelial–mesenchymal transition.

scholarly journals ATG9A Is Overexpressed in Triple Negative Breast Cancer and Its In Vitro Extinction Leads to the Inhibition of Pro-Cancer Phenotypes

Cells ◽  
2018 ◽  
Vol 7 (12) ◽  
pp. 248 ◽  
Author(s):  
Aurore Claude-Taupin ◽  
Leïla Fonderflick ◽  
Thierry Gauthier ◽  
Laura Mansi ◽  
Jean-René Pallandre ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Cancer Cell Line ◽  
Cancer Tissue ◽  
The Future ◽  
Cancer Phenotypes

Early detection and targeted treatments have led to a significant decrease in mortality linked to breast cancer (BC), however, important issues need to be addressed in the future. One of them will be to find new triple negative breast cancer (TNBC) therapeutic strategies, since none are currently efficiently targeting this subtype of BC. Since numerous studies have reported the possibility of targeting the autophagy pathway to treat or limit cancer progression, we analyzed the expression of six autophagy genes (ATG9A, ATG9B, BECLIN1, LC3B, NIX and P62/SQSTM1) in breast cancer tissue, and compared their expression with healthy adjacent tissue. In our study, we observed an increase in ATG9A mRNA expression in TNBC samples from our breast cancer cohort. We also showed that this increase of the transcript was confirmed at the protein level on paraffin-embedded tissues. To corroborate these in vivo data, we designed shRNA- and CRISPR/Cas9-driven inhibition of ATG9A expression in the triple negative breast cancer cell line MDA-MB-436, in order to determine its role in the regulation of cancer phenotypes. We found that ATG9A inhibition led to an inhibition of in vitro cancer features, suggesting that ATG9A can be considered as a new marker of TNBC and might be considered in the future as a target to develop new specific TNBC therapies.

scholarly journals Lamin B2 promotes the progression of triple negative breast cancer via mediating cell proliferation and apoptosis

2021 ◽  
Vol 41 (1) ◽  
Author(s):  
Cui-Cui Zhao ◽  
Jing Chen ◽  
Li-Ying Zhang ◽  
Hong Liu ◽  
Chuan-Gui Zhang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Cancer Progression ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
The Cancer Genome Atlas ◽  
Proliferation And Apoptosis

Abstract Triple negative breast cancer (TNBC) is a more common type of breast cancer with high distant metastasis and poor prognosis. The potential role of lamins in cancer progression has been widely revealed. However, the function of lamin B2 (LMNB2) in TNBC progression is still unclear. The present study aimed to investigate the role of LMNB2 in TNBC. The cancer genome atlas (TCGA) database analysis and immunohistochemistry (IHC) were performed to examine LMNB2 expression levels. LMNB2 short hairpin RNA plasmid or lentivirus was used to deplete the expression of LMNB2 in human TNBC cell lines including MDA-MB-468 and MDA-MB-231. Alterations in cell proliferation and apoptosis in vitro and the nude mouse tumorigenicity assay in vivo were subsequently analyzed. The human TNBC tissues shown high expression of LMNB2 according to the bioinformation analysis and IHC assays. LMNB2 expression was correlated with the clinical pathological features of TNBC patients, including pTNM stage and lymph node metastasis. Through in vitro and in vivo assays, we confirmed LMNB2 depletion suppressed the proliferation and induced the apoptosis of TNBC cells, and inhibited tumor growth of TNBC cells in mice, with the decrease in Ki67 expression or the increase in caspase-3 expression. In conclusion, LMNB2 may promote TNBC progression and could serve as a potential therapeutic target for TNBC treatment.

CircPLK1 sponges miR-296-5p to facilitate triple-negative breast cancer progression

Epigenomics ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 1163-1176 ◽  
Author(s):  
Yanan Kong ◽  
Lu Yang ◽  
Weidong Wei ◽  
Ning Lyu ◽  
Yutian Zou ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Expression Profiles ◽  
Proliferation And Metastasis ◽  
Underlying Mechanisms

Aim: To investigate the role of circRNAs in triple-negative breast cancer (TNBC) and the underlying mechanisms. Materials & methods: We performed circRNA microarrays to explore the expression profiles of TNBC cell lines. Experiments in vitro and in vivo were conducted to explore the effects of circPLK1 on tumor proliferation and metastasis as well as the interaction between circPLK1, miR-296-5p and PLK1 in TNBC. Results & conclusion: CircPLK1 was significantly upregulated in TNBC and associated with poor survivals. CircPLK1 knockdown inhibited cell growth and invasion in vitro as well as tumor occurrence and metastasis in vivo. CircPLK1-miR-296-5p- PLK1 axis regulates tumor progression by ceRNA mechanism in TNBC, indicating that circPLK1 may serve as a prognostic factor and novel therapeutic target for TNBC.

scholarly journals Mitotic kinesin-like protein 1, regulated by FOXM1, promotes triple negative breast cancer progression via activating Wnt/β-catenin pathway

2022 ◽  
Author(s):  
Zhi Li ◽  
Hai-Yan Yang ◽  
Xiao-Lan Zhang ◽  
Xu Zhang ◽  
Yu-Zhou Huang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Underlying Mechanism ◽  
Migration And Invasion ◽  
Cancer Proliferation ◽  
Tumor Growth And Metastasis

Abstract Background: Triple negative breast cancer (TNBC) is highly malignant and has a worse prognosis, compared with other subtypes of breast cancer due to the absence of therapeutic targets. MKLP1 plays a crucial role in tumorigenesis and cancer progression. However, the role of MKLP1 in triple negative breast cancer and the underlying mechanism remain unknown. The study aimed to elucidate the biological function regulatory mechanism of MKLP1 in triple negative breast cancerMethods: Quantitative real-time PCR and Western blotting were used to determine the MKLP1 expression in breast cancer tissues and cell lines. Then, functional experiments in vitro and in vivo were performed to investigate the effects of MKLP1 on tumor growth and metastasis in triple negative breast cancer. Chromatin immunoprecipitation assay was conducted to illustrate the potential regulatory mechanisms of MKLP1 in triple negative breast cancer.Results: We found that MKLP1 was significantly up-regulated and associated with poor prognosis in triple negative breast cancer. MKLP1 could promote triple negative breast cancer proliferation, migration and invasion in vitro and in vivo. MKLP1 could activate Wnt/β-catenin pathway and promote EMT progression. In addition, FOXM1, upregulated by WDR5 via H3K4me3 modification, directly bound to the promoter of MKLP1 gene to promote its transcription and accelerated TNBC progression via Wnt/β-catenin pathway. Both of small inhibitor of FOXM1 and WDR5 could inhibit TNBC progression. Conclusions: Our findings elucidate WDR5/FOXM1/MKLP1/Wnt/β-catenin axis is associated with TNBC progression and may provide a novel and promising therapeutic target for TNBC treatment.

scholarly journals Targeting neurons in the tumor microenvironment with bupivacaine nanoparticles reduces breast cancer progression and metastases

2021 ◽  
Author(s):  
Maya Kaduri ◽  
Mor Sela ◽  
Shaked Kagan ◽  
Maria Poley ◽  
Hanan Abumanhal-Masarweh ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Opioid Analgesic ◽  
Neurite Growth

Neurons within the tumor microenvironment promote cancer progression, thus their local targeting has potential clinical benefits. We designed PEGylated lipid nanoparticles loaded with a non-opioid analgesic, bupivacaine, to target neurons within breast cancer tumors and suppress nerve-to-cancer crosstalk. In vitro, 100-nm nanoparticles were taken up readily by primary neurons, trafficking from the neuronal body and along the axons. We demonstrate that signaling between triple-negative breast cancer cells (4T1) and neurons involves secretion of cytokines stimulating neurite outgrowth. Reciprocally, neurons stimulated 4T1 proliferation, migration and survival through secretion of neurotransmitters. Bupivacaine curbs neurite growth and signaling with cancer cells, inhibiting cancer-cell viability. In vivo, bupivacaine-loaded nanoparticles administered intravenously, suppressed neurons in orthotopic triple-negative breast cancer tumors, inhibiting tumor growth and metastatic dissemination. Overall, our findings suggest that reducing nerve involvement in tumors is important for treating cancer.

scholarly journals An in vitro–in vivo model of epithelial mesenchymal transition in triple negative breast cancer

2012 ◽  
Vol 9 (1-2) ◽  
pp. e35-e40 ◽  
Author(s):  
Yubo Zhai ◽  
Julia Santucci-Pereira ◽  
Ricardo Lopez de Cicco ◽  
Irma H. Russo ◽  
Jose Russo
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Epithelial Mesenchymal Transition ◽  
In Vivo Model ◽  
Mesenchymal Transition

scholarly journals PMEPA1/TMEPAI Is a Unique Tumorigenic Activator of AKT Promoting Proteasomal Degradation of PHLPP1 in Triple-Negative Breast Cancer Cells

Cancers ◽  
2021 ◽  
Vol 13 (19) ◽  
pp. 4934
Author(s):  
Md. Anwarul Haque ◽  
Mohammed Abdelaziz ◽  
Meidi Utami Puteri ◽  
Thanh Thao Vo Nguyen ◽  
Kosei Kudo ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Proteasomal Degradation ◽  
Ph Domain ◽  
Akt Activation ◽  
Tcga Dataset ◽  
Oncogenic Protein

Transmembrane prostate androgen-induced protein (TMEPAI), also known as PMEPA1, is highly expressed in many types of cancer and promotes oncogenic abilities. However, the mechanisms whereby TMEPAI facilitates tumorigenesis are not fully understood. We previously established TMEPAI-knockout (KO) cells from human triple-negative breast cancer (TNBC) cell lines and found that TMEPAI-KO cells showed reduced tumorigenic abilities. Here, we report that TMEPAI-KO cells upregulated the expression of pleckstrin homology (PH) domain and leucine-rich repeat protein phosphatase 1 (PHLPP1) and suppressed AKT Ser473 phosphorylation, which was consistent with TCGA dataset analysis. Additionally, the knockdown (KD) of PHLPP1 in TMEPAI-KO cells partially but significantly rescued AKT Ser473 phosphorylation, as well as in vitro and in vivo tumorigenic activities, thus showing that TMEPAI functions as an oncogenic protein through the regulation of PHLPP1 subsequent to AKT activation. Furthermore, we demonstrated that TMEPAI PPxY (PY) motifs are essential for binding to NEDD4-2, an E3 ubiquitin ligase, and PHLPP1-downregulatory ability. Moreover, TMEPAI enhanced the complex formation of PHLPP1 with NEDD4-2 and PHLPP1 polyubiquitination, which leads to its proteasomal degradation. These findings indicate that the PY motifs of TMEPAI suppress the amount of PHLPP1 and maintain AKT Ser473 phosphorylation at high levels to enhance the tumorigenic potentiality of TNBC.

The Potential of Natural Products in the Treatment of Triple-Negative Breast Cancer

2021 ◽  
Vol 22 ◽  
Author(s):  
Danny Yu Jia Ke ◽  
Sara El-Sahli ◽  
Lisheng Wang
Keyword(s):  
Breast Cancer ◽  
Natural Products ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Epithelial Mesenchymal Transition ◽  
Human Populations ◽  
Case Control Studies ◽  
Mesenchymal Transition

Abstract: Triple-negative breast cancer (TNBC) is a subtype of breast cancer that lacks receptors for targeted therapy. Consequently, chemotherapy is currently the mainstay of systemic treatment options. However, the enrichment of cancer stem cells (CSC, a subpopulation with stem-cell characteristics and tumor-initiating propensity) promotes chemo-resistance and tumorigenesis, resulting in cancer recurrence and relapse. Furthermore, toxic side effects of chemotherapeutics reduce patient wellbeing. Natural products, specifically compounds derived from plants, have the potential to treat TNBC and target CSCs by inhibiting CSC signaling pathways. Literature evidence from six promising compounds were reviewed, including sulforaphane, curcumin, genistein, resveratrol, lycopene, and epigallocatechin-3-gallate. These compounds have been shown to promote cell cycle arrest and apoptosis in TNBC cells. They also could inhibit the epithelial-mesenchymal transition (EMT) that plays an important role in metastasis. In addition, those natural compounds have been found to inhibit pathways important for CSCs, such as NF-κB, PI3K/Akt/mTOR, Notch 1, Wnt/β-catenin, and YAP. Clinicals trials conducted on these compounds have shown varying degrees of effectiveness. Epidemiological case-control studies for the compounds commonly consumed in certain human populations have also been summarized. While in vivo and in vitro data are promising, further basic and clinical investigations are required. Likely, natural products in combination with other drugs may hold great potential to improve TNBC treatment efficacy and patient outcomes.

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