scholarly journals In silico Analysis of Combinatorial microRNA Activity Reveals Target Genes and Pathways Associated with Breast Cancer Metastasis

2011 ◽  
Vol 10 ◽  
pp. CIN.S6631 ◽  
Author(s):  
Alan A. Dombkowski ◽  
Zakia Sultana ◽  
Douglas B. Craig ◽  
Hasan Jamil
Keyword(s):  
Breast Cancer ◽  
Cancer Metastasis ◽  
Target Genes ◽  
In Silico Analysis ◽  
Metastatic Potential ◽  
Breast Cancer Metastasis ◽  
Computational Method ◽  
Cytoskeleton Organization ◽  
Cellular Processes ◽  
Therapeutic Development

Aberrant microRNA activity has been reported in many diseases, and studies often find numerous microRNAs concurrently dysregulated. Most target genes have binding sites for multiple microRNAs, and mounting evidence indicates that it is important to consider their combinatorial effect on target gene repression. A recent study associated the coincident loss of expression of six microRNAs with metastatic potential in breast cancer. Here, we used a new computational method, miR-AT!, to investigate combinatorial activity among this group of microRNAs. We found that the set of transcripts having multiple target sites for these microRNAs was significantly enriched with genes involved in cellular processes commonly perturbed in metastatic tumors: cell cycle regulation, cytoskeleton organization, and cell adhesion. Network analysis revealed numerous target genes upstream of cyclin D1 and c-Myc, indicating that the collective loss of the six microRNAs may have a focal effect on these two key regulatory nodes. A number of genes previously implicated in cancer metastasis are among the predicted combinatorial targets, including TGFB1, ARPC3, and RANKL. In summary, our analysis reveals extensive combinatorial interactions that have notable implications for their potential role in breast cancer metastasis and in therapeutic development.

scholarly journals The Activity of KIF14, Mieap, and EZR in a New Type of the Invasive Component, Torpedo-Like Structures, Predetermines the Metastatic Potential of Breast Cancer

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1909
Author(s):  
Tatiana S. Gerashchenko ◽  
Sofia Y. Zolotaryova ◽  
Artem M. Kiselev ◽  
Liubov A. Tashireva ◽  
Nikita M. Novikov ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Cells ◽  
Cancer Metastasis ◽  
Ether Lipid ◽  
Metastatic Tumor ◽  
Metastatic Potential ◽  
Breast Cancer Metastasis ◽  
Breast Cancers ◽  
Invasive Component ◽  
Positive Expression

Intratumor morphological heterogeneity reflects patterns of invasive growth and is an indicator of the metastatic potential of breast cancer. In this study, we used this heterogeneity to identify molecules associated with breast cancer invasion and metastasis. The gene expression microarray data were used to identify genes differentially expressed between solid, trabecular, and other morphological arrangements of tumor cells. Immunohistochemistry was applied to evaluate the association of the selected proteins with metastasis. RNA-sequencing was performed to analyze the molecular makeup of metastatic tumor cells. High frequency of metastases and decreased metastasis-free survival were detected in patients either with positive expression of KIF14 or Mieap or negative expression of EZR at the tips of the torpedo-like structures in breast cancers. KIF14- and Mieap-positive and EZR-negative cells were mainly detected in the torpedo-like structures of the same breast tumors; however, their transcriptomic features differed. KIF14-positive cells showed a significant upregulation of genes involved in ether lipid metabolism. Mieap-positive cells were enriched in genes involved in mitophagy. EZR-negative cells displayed upregulated genes associated with phagocytosis and the chemokine-mediated signaling pathway. In conclusion, the positive expression of KIF14 and Mieap and negative expression of EZR at the tips of the torpedo-like structures are associated with breast cancer metastasis.

scholarly journals 4543 Glucocorticoid Receptors are essential effectors of TGFβ signaling in Triple Negative Breast Cancer

2020 ◽  
Vol 4 (s1) ◽  
pp. 7-8
Author(s):  
Carlos Jesus Perez Kerkvliet ◽  
Amy R Dwyer ◽  
Caroline Diep ◽  
Robert Oakley ◽  
Christopher Liddle ◽  
...  
Keyword(s):  
Breast Cancer ◽  
P38 Mapk ◽  
Cell Biology ◽  
Glucocorticoid Receptors ◽  
Cancer Metastasis ◽  
Target Genes ◽  
Mapk Signaling ◽  
Breast Cancer Metastasis ◽  
Tnbc Cell

OBJECTIVES/GOALS: The glucocorticoid receptor (GR) is a ubiquitous steroid hormone receptor that is emerging as a mediator of breast cancer metastasis. We aim to better understand the biology associated with phospho-GR species in TNBC and their contribution to tumor progression. METHODS/STUDY POPULATION: To better understand how p-S134 GR may impact TNBC cell biology, we probed GR regulation by soluble factors that are rich within the tumor microenvironment (TME), such as TGFβ. TNBC cells harboring endogenous wild-type or S134A-GR species were created by CRISPR/Cas knock-in and subjected to in vitro assays of advanced cancer behavior. RNA-Seq was employed to identify pS134-GR target genes that are uniquely regulated by TGFβ in the absence of exogenously added GR ligands. Direct regulation of selected TGFβ-induced pS134-GR target genes was validated accordingly. Bioinformatics tools were used to probe publicly available TNBC patient data sets for expression of a pS134-GR 24-gene signature. RESULTS/ANTICIPATED RESULTS: In the absence of GR ligands, GR is transcriptionally activated via p38-MAPK-dependent phosphorylation of Ser134 upon exposure of TNBC cells to TME-derived agents (TGFβ, HGF). The ligand-independent pS134-GR transcriptome primarily encompasses gene sets associated with TNBC cell survival and migration/invasion. Accordingly, pS134-GR was essential for TGFβ-induced TNBC cell migration, anchorage-independent growth in soft-agar, and tumorsphere formation, an in vitro readout of breast cancer stemness properties. Finally, a 24-gene pSer134-GR-dependent signature induced by TGFβ1 predicts shortened survival in breast cancer. We expect to find similar results using an in-house tissue microarray. DISCUSSION/SIGNIFICANCE OF IMPACT: Phospho-S134-GR is a critical downstream mediator of p38 MAPK signaling and TNBC migration, survival, and stemness properties. Our studies define GR as a required effector of TGFβ1 signaling and nominate pS134-GR as a biomarker of elevated risk of breast cancer dissemination.

scholarly journals E3 Ubiquitin Ligase NEDD4L Negatively Regulates Breast Cancer Metastasis By Downregulating SNAI2

2021 ◽  
Author(s):  
Baile Zuo ◽  
Ying Lan ◽  
Xiaoyan Li ◽  
Liping Zhao ◽  
Kexin Yu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Ubiquitin Ligase ◽  
Prognostic Model ◽  
Cancer Metastasis ◽  
Target Genes ◽  
Cox Regression ◽  
E3 Ubiquitin Ligase ◽  
Enrichment Analysis ◽  
Breast Cancer Metastasis ◽  
Independent Predictive Factor

Abstract Background Accumulating evidence demonstrated that the abnormal expression of E3-ubiquitin ligase NEDD4L plays an important role in the biological process of carcinomas. However, its role in breast cancer (BRCA) remains elusive. Methods The expression of NEDD4L was analyzed using BRCA datasets from public database. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were used for enrichment analysis. Both transwell assay and pulmonary metastasis model of BRCA were used to detect metastatic ability of cells. Western blotting, immunohistochemistry and immunofluorescence assay were used to detect the protein expression of target genes. The riskScore and nomogram were used to evaluate the prognosis of patients. Results NEDD4L was significantly downregulated in cancer tissues and positively correlated with the overall survival of patients. Knocking down NEDD4L could enhance the migration and metastasis ability of BRCA cells. SP1 promotes NEDD4L expression, resulting in SNAI2 downregulation in BRCA. A NEDD4L related to the prognostic model developed by LASSO Cox regression could be an independent predictive factor for BRCA. A nomogram combining riskScore and clinical indicators was established to evaluate the prognosis of BRCA quantitatively. Conclusions This study first reveals the role of the SP1/NEDD4L/SNAI2 axis in BRCA and establishes a reliable prognostic model, which provides a novel target and basis for clinical treatment and prognosis evaluation of breast cancer.

scholarly journals The histone H3K9 demethylase KDM3A promotes anoikis by transcriptionally activating pro-apoptotic genes BNIP3 and BNIP3L

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Victoria E Pedanou ◽  
Stéphane Gobeil ◽  
Sébastien Tabariès ◽  
Tessa M Simone ◽  
Lihua Julie Zhu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Epithelial Cells ◽  
Transcriptional Activation ◽  
Large Scale ◽  
Cancer Metastasis ◽  
Ectopic Expression ◽  
Metastatic Potential ◽  
Breast Cancer Metastasis ◽  
Integrin Signaling ◽  
Breast Cancer Cell Lines

Epithelial cells that lose attachment to the extracellular matrix undergo a specialized form of apoptosis called anoikis. Here, using large-scale RNA interference (RNAi) screening, we find that KDM3A, a histone H3 lysine 9 (H3K9) mono- and di-demethylase, plays a pivotal role in anoikis induction. In attached breast epithelial cells, KDM3A expression is maintained at low levels by integrin signaling. Following detachment, integrin signaling is decreased resulting in increased KDM3A expression. RNAi-mediated knockdown of KDM3A substantially reduces apoptosis following detachment and, conversely, ectopic expression of KDM3A induces cell death in attached cells. We find that KDM3A promotes anoikis through transcriptional activation of BNIP3 and BNIP3L, which encode pro-apoptotic proteins. Using mouse models of breast cancer metastasis we show that knockdown of Kdm3a enhances metastatic potential. Finally, we find defective KDM3A expression in human breast cancer cell lines and tumors. Collectively, our results reveal a novel transcriptional regulatory program that mediates anoikis.

scholarly journals TrkB Inhibits the BMP Signaling-Mediated Growth Inhibition of Cancer Cells

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2095
Author(s):  
Min Soo Kim ◽  
Wook Jin
Keyword(s):  
Breast Cancer ◽  
Growth Inhibition ◽  
Cancer Cells ◽  
Tumor Suppression ◽  
Cancer Metastasis ◽  
Metastatic Potential ◽  
Inhibitory Effect ◽  
Breast Cancer Metastasis ◽  
Bmp Signaling ◽  
Janus Kinase

We have previously observed that tropomyosin receptor kinase B (TrkB) induces breast cancer metastasis by activating both the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) and phosphatidylinositol-3-Kinase (PI3K)/AKT signaling pathways and inhibiting runt-related transcription factor 3 (RUNX3) and kelch-like ECH-associated protein 1 (KEAP1). These studies indicated that TrkB expression is crucial to the pathogenesis of breast cancer. However, how TrkB regulates bone morphogenetic protein (BMP) signaling and tumor suppression is largely unknown. Herein, we report that TrkB is a key regulator of BMP-mediated tumor suppression. TrkB enhances the metastatic potential of cancer cells by promoting cell anchorage-independent growth, migration, and suppressing BMP-2-mediated growth inhibition. TrkB inhibits the BMP-mediated activation of SMAD family member 1 (SMAD1) by promoting the formation of the TrkB/BMP type II receptor complex and suppresses RUNX3 by depleting BMP receptor I (BMPRI) expression. In addition, the knockdown of TrkB restored the tumor-inhibitory effect of BMP-2 via the activation of SMAD1. Moreover, the TrkB kinase activity was required for its effect on BMP signaling. Our study identified a unique role of TrkB in the regulation of BMP-mediated growth inhibition and BMP-2-induced RUNX3 expression.

Enhanced Metastatic Potential in a 3D Tissue Scaffold toward a Comprehensive in Vitro Model for Breast Cancer Metastasis

2015 ◽  
Vol 7 (50) ◽  
pp. 27810-27822 ◽  
Author(s):  
Gowri Manohari Balachander ◽  
Sai A. Balaji ◽  
Annapoorni Rangarajan ◽  
Kaushik Chatterjee
Keyword(s):  
Breast Cancer ◽  
In Vitro Model ◽  
Cancer Metastasis ◽  
Metastatic Potential ◽  
Breast Cancer Metastasis ◽  
Tissue Scaffold ◽  
Vitro Model

scholarly journals Metastasis: A Bane of Breast Cancer Therapy

2020 ◽  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Cancer Progression ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Tumour Size ◽  
Metastatic Breast ◽  
Metastatic Potential ◽  
Breast Cancer Metastasis ◽  
Mesenchymal Transition

The underlying mechanisms of metastasis in patients with breast cancer is still poorly understood. Approximately 6% of patients with breast cancer present with metastasis at the time of diagnosis. Metastatic breast cancer is difficult to treat and patients with breast cancer with distant metastasis have a significantly lower 5-year survival rate compared to patients with localised breast cancer (27% and 99%, respectively). During breast cancer progression, tumour cells first metastasise to nearby draining lymph nodes and then to distant organs, primarily bone, lungs, liver, and brain. In this brief review, the authors discuss breast cancer metastasis, the role of epithelial–mesenchymal transition and the contributions of the immune system to the metastatic process. The authors also briefly discuss whether there is any relationship between tumour size and metastatic potential, and recent advances in treatment for metastatic breast cancer. The studies highlighted suggest that immunotherapy may play a more significant role in future patient care for metastatic breast cancer.

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