scholarly journals ANLN Enhances Triple-Negative Breast Cancer Stemness Through TWIST1 and BMP2 and Promotes its Spheroid Growth

2021 ◽  
Vol 8 ◽  
Author(s):  
Alishba Maryam ◽  
Y. Rebecca Chin
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Molecular Mechanisms ◽  
Triple Negative ◽  
Specific Gene ◽  
Poor Survival ◽  
Cancer Stemness ◽  
Mammosphere Formation ◽  
Super Enhancer ◽  
Spheroid Growth

ANLN is frequently upregulated in triple-negative breast cancer (TNBC) and its high expression in tumors are significantly associated with poor survival and recurrence, thereby it has been proposed to function as a prognostic marker for breast cancer. However, the specific function and molecular mechanisms by which ANLN promotes TNBC tumorigenesis remain elusive. Using multiomic profiling, we recently uncovered ANLN as a TNBC-specific gene driven by super-enhancer. Here, by Crispr/Cas9 editing, we showed that knockout of ANLN inhibits spheroid growth of TNBC. Interestingly, its effect on cell proliferation in 2D cultures is minimal. ANLN depletion inhibits mammosphere formation and clonogenicity potently, suggesting its important function in regulating cancer stem cells (CSCs). We screened a panel of stem cell-related genes and uncovered several CSC genes regulated by ANLN. We further identify TWIST1 and BMP2 as essential genes that mediate ANLN’s function in stemness but not spheroid growth. These findings may contribute to search for effective targeted therapies to treat TNBC.

scholarly journals ITGA2is a target of miR-206 promoting cancer stemness and lung metastasis through enhancedACLYandCCND1expression in triple negative breast cancer

2019 ◽  
Author(s):  
Valery Adorno-Cruz ◽  
Andrew D. Hoffmann ◽  
Xia Liu ◽  
Brian Wray ◽  
Ruth A. Keri ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Lipid Metabolism ◽  
Lung Metastasis ◽  
Triple Negative Breast Cancer ◽  
Molecular Mechanisms ◽  
Triple Negative ◽  
Fatty Acid Biosynthesis ◽  
Migration And Invasion ◽  
Cancer Stemness

AbstractAccumulating evidence demonstrates that cancer stemness is essential for both tumor development and progression, regulated by multi-layer factors at genetic, epigenetic and micro-environmental levels. However, how to target stemness-driven plasticity and eliminate metastasis remains one of the biggest challenges in the clinic. We aim to identify novel molecular mechanisms underlying stemness of triple negative breast cancer (TNBC) which frequently metastasizes to the visceral organs but lacks targeted therapies. Following our previous discovery of miR-206 as an epigenetic suppressor of tumorigenesis and metastasis, we now report that the integrin receptor CD49b-encodingITGA2is an oncogenic target of miR-206 in TNBC.ITGA2knockdown abolished cancer stemness (mammosphere formation, pluripotency marker expression, and FAK phosphorylation), inhibited cell cycling, compromised migration and invasion, and thereby decreasing lung metastasis of TNBC. RNA sequencing analyses of breast cancer cells revealed thatITGA2knockdown inhibits gene expression essential for both classical integrin-regulated pathways (cell cycle, wounding response, protein kinase, etc) and newly identified pathways such as lipid metabolism. Notably,ACLY-encoded ATP citrate lyase is one of the top targets in CD49b-regulated lipid metabolism andCCND1-encoded Cyclin D1 represents regulation of cell cycle and many other pathways. ACLY, known to catalyze the formation of cytosolic acetyl-CoA for fatty acid biosynthesis, is indispensable for cancer stemness. Overexpression ofCCND1rescues the phenotype ofITGA2knockdown-induced cell cycle arrest. High expression levels of theITGA2/ACLY/CCND1axis are correlated with an unfavorable relapse-free survival of patients with high grade breast cancer, in both basal-like and other subtypes. This study identifiesITGA2as a potential therapeutic target of TNBC stemness and metastasis.

scholarly journals Defining super-enhancer landscape in triple-negative breast cancer by multiomic profiling

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Hao Huang ◽  
Jianyang Hu ◽  
Alishba Maryam ◽  
Qinghua Huang ◽  
Yuchen Zhang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Regulatory Elements ◽  
Breast Cancer Subtypes ◽  
Specific Gene ◽  
Breast Tumorigenesis ◽  
Cancer Subtypes ◽  
Super Enhancer

AbstractBreast cancer is a heterogeneous disease, affecting over 3.5 million women worldwide, yet the functional role of cis-regulatory elements including super-enhancers in different breast cancer subtypes remains poorly characterized. Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with a poor prognosis. Here we apply integrated epigenomic and transcriptomic profiling to uncover super-enhancer heterogeneity between breast cancer subtypes, and provide clinically relevant biological insights towards TNBC. Using CRISPR/Cas9-mediated gene editing, we identify genes that are specifically regulated by TNBC-specific super-enhancers, including FOXC1 and MET, thereby unveiling a mechanism for specific overexpression of the key oncogenes in TNBC. We also identify ANLN as a TNBC-specific gene regulated by super-enhancer. Our studies reveal a TNBC-specific epigenomic landscape, contributing to the dysregulated oncogene expression in breast tumorigenesis.

scholarly journals A novel humanized Frizzled-7-targeting antibody enhances antitumor effects of Bevacizumab against triple-negative breast cancer via blocking Wnt/β-catenin signaling pathway

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Wei Xie ◽  
Huijie Zhao ◽  
Fengxian Wang ◽  
Yiyun Wang ◽  
Yuan He ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Molecular Mechanisms ◽  
Near Infrared ◽  
Triple Negative ◽  
Vasculogenic Mimicry ◽  
Xenograft Model ◽  
Luciferase Reporter ◽  
Antitumor Effects ◽  
Mouse Xenograft Model

Abstract Background Anti-angiogenic therapy has been widely applied to the clinical treatment of malignant tumors. However, the efficacy of such treatments has been called into question, especially in triple-negative breast cancer (TNBC). Bevacizumab, the first anti-angiogenic agent approved by FDA, actually increases invasive and metastatic properties of TNBC cells, resulting from the activation of Wnt/β-catenin signaling in response to hypoxia. As a critical receptor of Wnt/β-catenin signaling, Frizzled-7 (Fzd7) is aberrantly expressed in TNBC, indicating Fzd7 a potential target for developing drugs to be combined with anti-angiogenic agents. Methods Hybridoma technique and antibody humanization technique were utilized to generate a Fzd7-targeting antibody (SHH002-hu1). Biolayer interferometry (BLI) assay and near infrared (NIR) imaging were conducted to detect the affinity and targeting ability of SHH002-hu1. Next, whether SHH002-hu1 could suppress the invasion and migration of TNBC cells induced by Bevacizumab were validated, and the underlying molecular mechanisms were elucidated by luciferase reporter and western blot assays. The nude-mice transplanted TNBC models were established to assess the anti-TNBC activities of SHH002-hu1 when combined with Bevacizumab. Then, the effects on putative TNBC stem-like cells and Wnt/β-catenin signaling were evaluated by immunofluorescence (IF). Further, the tumor-initiating and self-renew capacity of TNBC cells were studied by secondary nude mouse xenograft model and sphere formation assay. In addition, the effects of SHH002-hu1 on the adaptation of TNBC cells to hypoxia were evaluated by the detection of vasculogenic mimicry (VM) and hypoxia-inducible factor-1α (HIF-1α) transcriptional activity. Results The novel humanized antibody targeting Fzd7 (SHH002-hu1) exhibited extremely high affinity with Fzd7, and specifically targeted to Fzd7+ cells and tumor tissues. SHH002-hu1 repressed invasion, migration and epithelial-mesenchymal cell transformation (EMT) of TNBC cells induced by Bevacizumab through abating Wnt/β-catenin signaling. SHH002-hu1 significantly enhanced the capacity of Bevacizumab to inhibit the growth of TNBC via reducing the subpopulation of putative TNBC stem-like cells, further attenuating Bevacizumab-enhanced tumor-initiating and self-renew capacity of TNBC cells. Moreover, SHH002-hu1 effectively restrained the adaptation of TNBC cells to hypoxia via disrupting Wnt/β-catenin signaling. Conclusion SHH002-hu1 significantly enhances the anti-TNBC capacity of Bevacizumab, and shows the potential of preventing TNBC recurrence, suggesting SHH002-hu1 a good candidate for the synergistic therapy together with Bevacizumab.

scholarly journals MiR-211 determines brain metastasis specificity through SOX11/NGN2 axis in triple-negative breast cancer

Oncogene ◽  
2021 ◽  
Author(s):  
Jhih-Kai Pan ◽  
Cheng-Han Lin ◽  
Yao-Lung Kuo ◽  
Luo-Ping Ger ◽  
Hui-Chuan Cheng ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Brain Metastasis ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Survival Outcomes ◽  
Poor Survival ◽  
Breast Cancer Brain Metastasis ◽  
High Level

AbstractBrian metastasis, which is diagnosed in 30% of triple-negative breast cancer (TNBC) patients with metastasis, causes poor survival outcomes. Growing evidence has characterized miRNAs involving in breast cancer brain metastasis; however, currently, there is a lack of prognostic plasma-based indicator for brain metastasis. In this study, high level of miR-211 can act as brain metastatic prognostic marker in vivo. High miR-211 drives early and specific brain colonization through enhancing trans-blood–brain barrier (BBB) migration, BBB adherence, and stemness properties of tumor cells and causes poor survival in vivo. SOX11 and NGN2 are the downstream targets of miR-211 and negatively regulate miR-211-mediated TNBC brain metastasis in vitro and in vivo. Most importantly, high miR-211 is correlated with poor survival and brain metastasis in TNBC patients. Our findings suggest that miR-211 may be used as an indicator for TNBC brain metastasis.

scholarly journals Syndecan-1 Promotes Angiogenesis in Triple-Negative Breast Cancer through the Prognostically Relevant Tissue Factor Pathway and Additional Angiogenic Routes

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2318
Author(s):  
Eyyad Nassar ◽  
Nourhan Hassan ◽  
Eslam A. El-Ghonaimy ◽  
Hebatallah Hassan ◽  
Mahmoud Salah Abdullah ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tissue Factor ◽  
Cell Lines ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Network Formation ◽  
Umbilical Vein ◽  
Poor Survival ◽  
Altered Expression ◽  
Basal Breast Cancer

Triple-negative breast cancer (TNBC) is characterized by increased angiogenesis, metastasis, and poor survival. Dysregulation of the cell surface heparan sulfate proteoglycan and signaling co-receptor Syndecan-1 is linked to poor prognosis. To study its role in angiogenesis, we silenced Syndecan-1 in TNBC cell lines using a 3D human umbilical vein endothelial cell (HUVEC) co-culture system. Syndecan-1 siRNA depletion in SUM-149, MDA-MB-468, and MDA-MB-231 cells decreased HUVEC tubule network formation. Angiogenesis array revealed reduced VEGF-A and tissue factor (TF) in the Syndecan-1-silenced secretome. qPCR independently confirmed altered expression of F3, F7, F2R/PAR1, F2RL1/PAR2, VEGF-A, EDN1, IGFBP1, and IGFBP2 in SUM-149, MDA-MB-231, and MDA-MB-468 cells. ELISA revealed reduced secreted endothelin-1 (SUM-149, MDA-MB-468) and TF (all cell lines) upon Syndecan-1 depletion, while TF pathway inhibitor treatment impaired angiogenesis. Survival analysis of 3951 patients demonstrated that high expression of F3 and F7 are associated with better relapse-free survival, whereas poor survival was observed in TNBC and p53 mutant basal breast cancer (F3) and in ER-negative and HER2-positive breast cancer (F2R, F2RL1). STRING protein network analysis revealed associations of Syndecan-1 with VEGF-A and IGFBP1, further associated with the TF and ET-1 pathways. Our study suggests that TNBC Syndecan-1 regulates angiogenesis via the TF and additional angiogenic pathways and marks its constituents as novel prognostic markers and therapeutic targets.

scholarly journals Mibefradil inhibits the proliferation of triple-negative breast cancer by targeting AURKA to regulate apoptosis signal pathway

2021 ◽  
Author(s):  
Xu Han ◽  
Xiujuan Qu ◽  
Beixing Liu ◽  
Yizhe Wang ◽  
Yang Cheng ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Molecular Docking ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Therapeutic Drug ◽  
Specific Gene ◽  
In Vivo Models

Abstract Background: Triple negative breast cancer (TNBC) is a tumor characterized by high recurrence and mortality, but without effective targeted therapy. It is urgent to explore new treatment strategy to improve the efficacy of TNBC therapy. Methods: Transcriptomic profiling datasets of TNBC were used for screening TNBC specific gene sets. Drug prediction was performed in Connectivity map (CMap) database. Molecular docking method was used for analyzing drug targets. In vitro and in vivo models of TNBC were constructed to examine the drug efficacy. Results: We screened out Mibefradil, a T-type Ca2+ channel blocker, might be a potential therapeutic drug for TNBC by transcriptomics and bioinformatics analysis, and verified that Mibefradil could inhibit the proliferation of TNBC cells by inducing apoptosis and cell cycle arrest. Furthermore, by network pharmacology and molecular docking analysis, AURKA was predicted as the most possible drug target of Mibefradil. Finally, it was proved that Mibefradil treatment could induce apoptosis by decreasing protein expression and phosphorylation level of AURKA in vitro and in vivo. Conclusions: Mibefradil played anti-cancer role in TNBC cells by targeting to AURKA to induce cell cycle and apoptosis. Our results repurposed Mibefradil as a potential targeted drug of TNBC and provided a fundamental research for a novel strategy TNBC treatment.

scholarly journals Increased macroH2A1.1 Expression Correlates with Poor Survival of Triple-Negative Breast Cancer Patients

PLoS ONE ◽  
2014 ◽  
Vol 9 (6) ◽  
pp. e98930 ◽  
Author(s):  
Anne-Claire Lavigne ◽  
Magali Castells ◽  
Jérôme Mermet ◽  
Silvia Kocanova ◽  
Mathieu Dalvai ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Breast Cancer Patients ◽  
Poor Survival

scholarly journals A Polyphenol Rich Muscadine Grape Extract Reduces Triple Negative Breast Cancer Cell Migration in Association with Changes in Cell Morphology and Motility-Related Proteins

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 325-325
Author(s):  
Patricia Gallagher ◽  
Marianne Collard ◽  
Heather Brown-Harding ◽  
Elisabeth Tallant
Keyword(s):  
Breast Cancer ◽  
Cell Migration ◽  
Confocal Microscopy ◽  
Triple Negative Breast Cancer ◽  
Cell Shape ◽  
Molecular Mechanisms ◽  
Triple Negative ◽  
Dependent Manner ◽  
Grape Extract ◽  
Muscadine Grape

Abstract Objectives Triple negative breast cancer (TNBC) is a subtype of breast cancer characterized by the lack of estrogen receptors, progesterone receptors and over-expression of the human epidermal growth factor receptor 2, limiting targeted treatment.  TNBC disproportionally affects ethnic minorities and younger women and has a high propensity to metastasize, often within 5 years of diagnosis, making it one of the most aggressive breast cancer subtypes.  We showed that treatment with a proprietary muscadine grape extract (MGE) reduced the growth and metastasis of TNBC in mice.  Muscadine grapes (V. Rotundifolia) are rich in polyphenols and extracts produced from muscadine grape seed and skin are marketed as nutraceuticals for their anti-oxidant, anti-inflammatory, and anti-cancer properties.  The goal of these studies was to determine the molecular mechanisms for the reduction in metastatic growth by MGE. Methods A proprietary extract was prepared from muscadine grape seeds and skins.  Migration of MDA-MB-231 and BT-549 cells was measured by a scratch wound assay, cell shape was visualized by confocal microscopy and mRNA/proteins that participate in cell migration/motility were measured by RT-PCR and western blot hybridization. Results The extract reduced the migration of MDA-MB-231 and BT-549 TNBC cells in a dose-dependent manner.  The reduction in cell migration was associated with MGE-induced alterations in cell shape and actin filament organization, visualized by confocal microscopy.  The extract caused an apparent loss of cell polarization in MDA-MB-231 cells and a reduction in the presence of filopodia in BT-549 cells.  The MGE-induced reduction in migration and alterations in cell shape and polarization were associated with a decrease in Rho kinase ROCK1/2 mRNA and protein as well as both the mRNA and protein expression of RHAMM, a protein that is implicated in both cell motility and breast cancer progression. Conclusions These results demonstrate that a proprietary MGE reduces TNBC cell migration, in association with changes in cell shape and cytoskeleton as well as proteins that regulate migration and motility, suggesting that treatment of TNBC patients with MGE may slow or prevent metastatic progression. Funding Sources Chronic Disease Research Fund.

scholarly journals IGF-1/IGF-1R/FAK/YAP Transduction Signaling Prompts Growth Effects in Triple-Negative Breast Cancer (TNBC) Cells

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 1010 ◽  
Author(s):  
Damiano Cosimo Rigiracciolo ◽  
Nijiro Nohata ◽  
Rosamaria Lappano ◽  
Francesca Cirillo ◽  
Marianna Talia ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Triple Negative ◽  
Cancer Genomics ◽  
Treatment Options ◽  
Signal Transduction Pathway ◽  
Growth Potential ◽  
Nuclear Accumulation

Triple-negative breast cancer (TNBC) is an aggressive breast tumor subtype that currently lacks targeted treatment options. The role played by the insulin-like growth factor-1 (IGF-1) and its cognate receptor IGF-1R in TNBC has been reported. Nevertheless, the molecular mechanisms by which the IGF-1/IGF-1R system may contribute to TNBC progression still remains to be fully understood. By computational analysis of the vast cancer genomics information in public databases (TCGA and METABRIC), we obtained evidence that high IGF-1 or IGF-1R levels correlate with a worse clinical outcome in TNBC patients. Further bioinformatics analysis revealed that both the focal adhesion and the Hippo pathways are enriched in TNBC harboring an elevated expression of IGF-1 or IGF-1R. Mechanistically, we found that in TNBC cells, the IGF-1/IGF-1R system promotes the activation of the FAK signal transduction pathway, which in turn regulates the nuclear accumulation of YAP (yes-associated protein/yes-related protein) and the expression of its target genes. At the biological level, we found that the IGF-1/IGF-1R-FAK-YAP network cascade triggers the growth potential of TNBC cells, as evaluated in different experimental systems. Overall, our results suggest that the IGF-1/IGF-1R/FAK/YAP axis may contribute to the progression of the aggressive TNBC subtype.

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