Purinergic mechanisms in breast cancer metastasis.

2011 ◽  
Vol 29 (27_suppl) ◽  
pp. 229-229
Author(s):  
I. L. Buxton
Keyword(s):  
Breast Cancer ◽  
Endothelial Cells ◽  
Receptor Antagonist ◽  
Cancer Metastasis ◽  
Purinergic Receptor ◽  
Receptor Activation ◽  
Breast Cancer Metastasis ◽  
Breast Cancer Cell Lines ◽  
Breast Cancers ◽  
Human Endothelial Cells

229 Background: Breast cancers survive in patients in a dormant state only to grow as metastatic disease in the future. Surgery to remove the primary tumor often terminates dormancy resulting in accelerated relapses. Many breast cancer deaths might be averted if we understand the cellular mechanisms underlying escape from dormancy. We have proposed that extracellular nucleotide signaling constitutes a pathological axis from the transformed tumor cell to the endothelium in the service of intravasation, dissemination, extravasation and angiogenesis. We demonstrate a role for the dinucleotide kinase NM23/NDPK in the generation of signals that stimulate angiogenesis and escape from latency. Methods: We have employed protein purification and identification by Western blot, tubulogenesis, migration and proliferation assays in human endothelial cells, signaling assays of receptor activation, nucleotide and receptor transactivation/phosphorylation assays and tumor growth and metastasis imaging in immunocompromized mice (SCID) to establish a role of r nucleotides in breast cancer metastasis. Results: A panel of breast cancer cell lines, but not normal breast cells, shed/secrete large amounts of NM23 that is active as an ADP transphosphorylase. NM23 stimulates tubulogenesis, proliferation and migration in cultures of human endothelial cells in a manner blocked by purinergic receptor antagonist, inhibitors of the nucleoside diphosphate kinase activity of NM23, or by VEGFR2 antagonists. In SCID mice carrying MDA-MB-231 luciferase over-expressing breast cancers, NM23 appears in the blood early in tumorigenesis. Treatment with the P2Y1 receptor antagonist MRS2179, or the NM23 antagonist ellagic acid slows the growth of primary breast tumors and prevents metastatic tumor formation. Conclusions: NM23 secretion leading to nucleotide generation activates endothelial P2Y1 receptors resulting in transactivation of VEGFR2 and angiogenesis in support of metastasis. Identification of Nm23 as a marker of early of breast cancer development and blockade of the extracellular actions of NM23 offer a new approach to breast cancer detection and treatment.

scholarly journals WNK1 Enhances Migration and Invasion in Breast Cancer Models

2021 ◽  
Author(s):  
Ankita B. Jaykumar ◽  
Jiung Jung ◽  
Pravat Parida ◽  
Tuyen T. Dang ◽  
Magdalena Grzemska ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Metastasis ◽  
Breast Cancer Metastasis ◽  
Migration And Invasion ◽  
Breast Cancer Cell Lines ◽  
Breast Cancers ◽  
Breast Cancer Patients ◽  
Collagen Matrices ◽  
Cancer Models ◽  
Protein Components

AbstractMetastasis is the major cause of mortality in breast cancer patients. Many signaling pathways have been linked to cancer invasiveness, but blockade of few protein components has succeeded in reducing metastasis. Thus, identification of proteins contributing to invasion that are manipulable by small molecules may be valuable in inhibiting spread of the disease. The protein kinase WNK1 (with no lysine (K) 1) has been suggested to induce migration of cells representing a range of cancer types. Analyses of mouse models and patient data have implicated WNK1 as one of a handful of genes uniquely linked to invasive breast cancer. Here we present evidence that inhibition of WNK1 slows breast cancer metastasis. We show that depletion or inhibition of WNK1 reduces migration of several breast cancer cell lines in wound healing assays and decreases invasion in collagen matrices. Furthermore, WNK1 depletion suppresses expression of AXL, a tyrosine kinase implicated in metastasis. Finally, we demonstrate that WNK inhibition in mice attenuates tumor progression and metastatic burden. These data showing reduced migration, invasion, and metastasis upon WNK1 depletion in multiple breast cancer models suggest that WNK1 contributes to the metastatic phenotype and that WNK1 inhibition may offer a therapeutic avenue for attenuating progression of invasive breast cancers.

scholarly journals Rare case of invasive lobular breast cancer metastasis to the endometrium

2020 ◽  
Vol 48 (2-3) ◽  
pp. 116-118
Author(s):  
Damir Danolić ◽  
◽  
Luka Marcelić ◽  
Ilija Alvir ◽  
Ivica Mamić ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Metastasis ◽  
Metastatic Cancer ◽  
Female Genital Tract ◽  
Breast Cancer Metastasis ◽  
Breast Cancers ◽  
Endometrial Sampling ◽  
Invasive Lobular Breast Cancer ◽  
Postmenopausal Vaginal Bleeding ◽  
Female Genital

Metastases to the female genital tract from extra-genital primary cancers are uncommon and usually occur during widespread metastatic disease. Breast cancers are the most frequent primaries, predominantly the lobular type. Here, we report a case of a 55-year-old woman with breast cancer endometrial metastasis who presented with postmenopausal vaginal bleeding. We highlight the importance of endometrial sampling to confirm the diagnosis and distinguish primary from metastatic cancer of the endometrium since the treatment and prognosis of these conditions are entirely different.

BRMS1L inhibits bone metastasis of breast cancer cells through epigenetic silence of CXCR4.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e13002-e13002
Author(s):  
Yinghuan Cen ◽  
Chang Gong ◽  
Jun Li ◽  
Gehao Liang ◽  
Zihao Liu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Bone Metastasis ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Cancer Metastasis ◽  
Breast Cancer Metastasis ◽  
Breast Cancer Cell Lines ◽  
Breast Cancer Patients ◽  
Qrt Pcr ◽  
Metastatic Sites

e13002 Background: We previously demonstrated that BRMS1L (breast cancer metastasis suppressor 1 like) suppresses breast cancer metastasis through HDAC1 recruitment and histone H3K9 deacetylation at the promoter of FZD10, a receptor for Wnt signaling. It is still unclear whether BRMS1L regulates organ-specific metastases, such as bone metastasis, the most prevalent metastatic site of breast cancer. Methods: Examination of the expression of BRMS1L in primary tumors, bone metastatic and other metastatic tissues from breast cancer patients was implemented using qRT-PCR and immunohistochemistry staining. To investigate the mechanism by which BRMS1L drives breast cancer bone metastasis, we tested the mRNA expression by qRT-PCR of a set of potential bone related genes (BRGs) based on PubMed database in MDA-MB-231 cells over expressing BRMS1L and MCF-7 cells knocking-down BRMS1L, and detected the expression of CXCR4 in these established cells by western blot. Transwell assays were performed to assess the migration abilities of breast cancer cells towards osteoblasts. ChIP (Chromatin Immuno-Precipitation) were employed to test the interaction between BRMS1L and CXCR4. Results: At both mRNA and protein levels, the expression of BRMS1L was significantly lower in bone metastatic sites than that in primary cancer tissues and other metastatic sites of breast cancer patients. CXCR4 was screened out in a set of BRGs and negatively correlated with the expression of BRMS1L in breast cancer cell lines. BRMS1L inhibited the migration of breast cancer cells towards osteoblasts through CXCL12/CXCR4 axis. In the presence of TSA treatment, breast cancer cell lines showed an increased expression of CXCR4 in a TSA concentration-dependent manner. In addition, ChIP assays verified that BRMS1L directly bound to the promoter region of CXCR4 and inhibited its transcription through promoter histone deacetylation. Conclusions: BRMS1L mediates the migration abilities of breast cancer cells to bone microenvironment via targeting CXCR4 and contributes to bone metastasis of breast cancer cells. Thus, BRMS1L may be a potential biomarker for predicting bone metastasis in breast cancer.

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 Integrating Protein-Protein Interaction Networks with Gene- Gene Co-Expression Networks improves Gene Signatures for Classifying Breast Cancer Metastasis

2011 ◽  
Vol 8 (2) ◽  
pp. 222-238 ◽  
Author(s):  
Erik van den Akker ◽  
Bas Verbruggen ◽  
Bas Heijmans ◽  
Marian Beekman ◽  
Joost Kok ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Cancer Metastasis ◽  
Gene Selection ◽  
De Novo ◽  
Tumor Development ◽  
Interaction Network ◽  
Breast Cancer Metastasis ◽  
Breast Cancers ◽  
Proteinprotein Interaction

Summary Multiple studies have illustrated that gene expression profiling of primary breast cancers throughout the final stages of tumor development can provide valuable markers for risk prediction of metastasis and disease sub typing. However, the identification of a biologically interpretable and universally shared set of markers proved to be difficult. Here, we propose a method for de novo grouping of genes by dissecting the proteinprotein interaction network into disjoint sub networks using pair wise gene expression correlation measures. We show that the obtained sub networks are functionally coherent and are consistently identified when applied on a compendium composed of six different breast cancer studies. Application of the proposed method using different integration approaches underlines the robustness of the identified sub network related to cell cycle and identifies putative new sub network markers for metastasis related to cell-cell adhesion, the proteasome complex and JUN-FOS signalling. Although gene selection with the proposed method does not directly improve upon previously reported cross study classification performances, it shows great promises for applications in data integration and result interpretation.

scholarly journals The long non-coding RNA ET-20 mediates EMT by impairing desmosomes in breast cancer cells

2021 ◽  
Author(s):  
Meera Saxena ◽  
Mizue Hisano ◽  
Melanie Neutzner ◽  
Maren Diepenbruck ◽  
Robert Ivanek ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Matrix Protein ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Breast Cancer Metastasis ◽  
Breast Cancer Cell Lines ◽  
Mesenchymal Transition ◽  
Invasive Human Breast Cancer

The vast majority of breast cancer-associated deaths are due to metastatic spread of cancer cells, a process aided by epithelial-mesenchymal transition (EMT). Mounting evidence has indicated that long non-coding RNAs (lncRNAs) also contribute to tumor progression. We report the identification of 114 novel lncRNAs that change their expression during TGFβ-induced EMT in murine breast cancer cells (referred to as EMT-associated transcripts; ETs). Of these, the ET-20 gene localizes in antisense orientation within the Tenascin C (Tnc) gene locus. Tnc is an extra-cellular matrix protein which is critical for EMT and metastasis formation. Both ET-20 and Tnc are regulated by the EMT master transcription factor Sox4. Notably, ablation of ET-20 lncRNA effectively blocks Tnc expression and with it EMT. Mechanistically, ET-20 interacts with desmosomal proteins, thereby impairing epithelial desmosomes and promoting EMT. A short transcript variant of ET-20 is found upregulated in invasive human breast cancer cell lines where it also promotes EMT. Targeting ET-20 appears a therapeutically attractive lead to restrain EMT and breast cancer metastasis in addition to its potential utility as a biomarker for invasive breast cancer.

scholarly journals Therapy-induced senescence in normal tissue promotes breast cancer metastasis

2020 ◽  
Author(s):  
Douglas W. Perkins ◽  
Syed Haider ◽  
David Robertson ◽  
Richard Buus ◽  
Lynda O’Leary ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Normal Tissue ◽  
Systemic Chemotherapy ◽  
Cancer Metastasis ◽  
Resistance Mechanisms ◽  
Breast Cancer Metastasis ◽  
Breast Cancers ◽  
Stromal Fibroblasts

SummaryDisseminated tumour cells, particularly in ER+ breast cancers, typically exhibit a period of dormancy that renders them insensitive to targeting by chemotherapy. Additionally, chemotherapy treatment can result in normal tissue damage, including the induction of cellular senescence. Using mouse and human breast cancer models, we demonstrate that systemic chemotherapy administration results in accumulation of long-lived senescent stromal fibroblasts and promotes metastatic outgrowth. Chemotherapy-induced senescent fibroblasts upregulate a senescence associated secretory phenotype (SASP) that accelerates 3D tumour spheroid growth by stimulating mitogenic signalling. Senolytic drugs can effectively eliminate chemotherapy-induced senescent fibroblasts in vitro, but show only modest efficacy in vivo, at least in part due to the upregulation of resistance mechanisms. In conclusion, systemic chemotherapy can establish a productive microenvironment for colonisation and outgrowth of disseminated cancer cells, however, optimisation of senotherapies for effective targeting of senescent fibroblasts is required to establish them as useful additions to standard chemotherapy.

Targeting Monoacylglycerol Lipase in Triple Negative Breast Cancer Reduced Tumor-Associated Inflammation, Tumor Growth and Tumor Colonization in the Brain

2021 ◽  
Author(s):  
Othman Benchama ◽  
Sergiy Tyukhtenko ◽  
Michael S. Malamas ◽  
Mark K. Williams ◽  
Alexandros Makriyannis ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Growth ◽  
Cancer Metastasis ◽  
Triple Negative ◽  
Breast Cancer Metastasis ◽  
Monoacylglycerol Lipase ◽  
Breast Cancers ◽  
Novel Treatments ◽  
The Brain

Abstract While the prevalence of breast cancer metastasis in the brain is significantly higher in triple negative breast cancers (TNBCs), there is a lack of novel and/or improved therapies for these patients. Monoacylglycerol lipase (MAGL) is a hydrolase involved in lipid metabolism that catalyzes the degradation of 2-arachidonoylglycerol (2-AG) linked to generation of pro- and anti-inflammatory molecules. Here, we targeted MAGL in TNBCs, using the selective MAGL inhibitor AM9928 (hMAGL IC50 = 9nM, with prolonged pharmacodynamic effects of 46 hours residence time). AM9928 blocked TNBC cell adhesion and transmigration across human brain microvascular endothelial cells (HBMECs) in 3D co-cultures. In addition, AM9928 inhibited the secretion of IL-6, IL-8, and VEGF-A from TNBC cells. TNBC-derived exosomes activated HBMECs resulting in secretion of elevated levels of IL-8 and VEGF, which were inhibited by AM9928. Knockdown of MAGL by siRNA or treatment with AM9928 increased the expression of the adherent junction E-cadherin, known to be regulated by MAGL. Using in vivo studies of syngeneic GFP-4T1-BrM5 mammary tumor cells, AM9928 inhibited tumor growth in the mammary fat pads and attenuated blood brain barrier (BBB) permeability changes, resulting in reduced TNBC colonization in brain. Together, these results support the potential clinical application of MAGL inhibitors as novel treatments for TNBC.

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