scholarly journals Breast Cancer: An Examination of the Potential of ACKR3 to Modify the Response of CXCR4 to CXCL12

2018 ◽  
Vol 19 (11) ◽  
pp. 3592 ◽  
Author(s):  
Irene del Molino del Barrio ◽  
Georgina Wilkins ◽  
Annette Meeson ◽  
Simi Ali ◽  
John Kirby
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Chemokine Receptor ◽  
Chinese Hamster ◽  
Cellular Migration ◽  
Receptor Internalization ◽  
Calcium Flux ◽  
Akt Phosphorylation ◽  
Erk Phosphorylation ◽  
Chemokine Cxcl12

Upon binding with the chemokine CXCL12, the chemokine receptor CXCR4 has been shown to promote breast cancer progression. This process, however, can be affected by the expression of the atypical chemokine receptor ACKR3. Given ACKR3’s ability to form heterodimers with CXCR4, we investigated how dual expression of both receptors differed from their lone expression in terms of their signalling pathways. We created single and double CXCR4 and/or ACKR3 Chinese hamster ovary (CHO) cell transfectants. ERK and Akt phosphorylation after CXCL12 stimulation was assessed and correlated with receptor internalization. Functional consequences in cell migration and proliferation were determined through wound healing assays and calcium flux. Initial experiments showed that CXCR4 and ACKR3 were upregulated in primary breast cancer and that CXCR4 and ACKR3 could form heterodimers in transfected CHO cells. This co-expression modified CXCR4’s Akt activation after CXCL12’s stimulation but not ERK phosphorylation (p < 0.05). To assess this signalling disparity, receptor internalization was assessed and it was observed that ACKR3 was recycled to the surface whilst CXCR4 was degraded (p < 0.01), a process that could be partially inhibited with a proteasome inhibitor (p < 0.01). Internalization was also assessed with the ACKR3 agonist VUF11207, which caused both CXCR4 and ACKR3 to be degraded after internalization (p < 0.05 and p < 0.001), highlighting its potential as a dual targeting drug. Interestingly, we observed that CXCR4 but not ACKR3, activated calcium flux after CXCL12 stimulation (p < 0.05) and its co-expression could increase cellular migration (p < 0.01). These findings suggest that both receptors can signal through ERK and Akt pathways but co-expression can alter their kinetics and internalization pathways.

scholarly journals Involvement of the ERK/HIF-1α/EMT Pathway in XCL1-Induced Migration of MDA-MB-231 and SK-BR-3 Breast Cancer Cells

2020 ◽  
Vol 22 (1) ◽  
pp. 89
Author(s):  
Ha Thi Thu Do ◽  
Jungsook Cho
Keyword(s):  
Breast Cancer ◽  
Cell Migration ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Chemokine Receptor ◽  
Intracellular Signaling ◽  
Breast Cancer Cells ◽  
Epithelial Mesenchymal Transition ◽  
Mitogen Activated Protein Kinase ◽  
Mesenchymal Transition

Chemokine–receptor interactions play multiple roles in cancer progression. It was reported that the overexpression of X-C motif chemokine receptor 1 (XCR1), a specific receptor for chemokine X-C motif chemokine ligand 1 (XCL1), stimulates the migration of MDA-MB-231 triple-negative breast cancer cells. However, the exact mechanisms of this process remain to be elucidated. Our study found that XCL1 treatment markedly enhanced MDA-MB-231 cell migration. Additionally, XCL1 treatment enhanced epithelial–mesenchymal transition (EMT) of MDA-MB-231 cells via E-cadherin downregulation and upregulation of N-cadherin and vimentin as well as increases in β-catenin nucleus translocation. Furthermore, XCL1 enhanced the expression of hypoxia-inducible factor-1α (HIF-1α) and phosphorylation of extracellular signal-regulated kinase (ERK) 1/2. Notably, the effects of XCL1 on cell migration and intracellular signaling were negated by knockdown of XCR1 using siRNA, confirming XCR1-mediated actions. Treating MDA-MB-231 cells with U0126, a specific mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor, blocked XCL1-induced HIF-1α accumulation and cell migration. The effect of XCL1 on cell migration was also evaluated in ER-/HER2+ SK-BR-3 cells. XCL1 also promoted cell migration, EMT induction, HIF-1α accumulation, and ERK phosphorylation in SK-BR-3 cells. While XCL1 did not exhibit any significant impact on the matrix metalloproteinase (MMP)-2 and -9 expressions in MDA-MB-231 cells, it increased the expression of these enzymes in SK-BR-3 cells. Collectively, our results demonstrate that activation of the ERK/HIF-1α/EMT pathway is involved in the XCL1-induced migration of both MDA-MB-231 and SK-BR-3 breast cancer cells. Based on our findings, the XCL1–XCR1 interaction and its associated signaling molecules may serve as specific targets for the prevention of breast cancer cell migration and metastasis.

scholarly journals Structure–function analysis of LIV-1, the breast cancer-associated protein that belongs to a new subfamily of zinc transporters

2003 ◽  
Vol 375 (1) ◽  
pp. 51-59 ◽  
Author(s):  
Kathryn M. TAYLOR ◽  
Helen E. MORGAN ◽  
Andrea JOHNSON ◽  
Lisa J. HADLEY ◽  
Robert I. NICHOLSON
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Mammalian Cells ◽  
Function Analysis ◽  
Chinese Hamster Ovary Cells ◽  
Consensus Sequence ◽  
Chinese Hamster ◽  
Protein Product ◽  
Zinc Transporters ◽  
Regional Lymph Nodes

The LIV-1 gene has been previously associated with oestrogen-positive breast cancer and its metastatic spread to the regional lymph nodes. We have investigated the protein product of this gene as a marker for disease progression of breast cancer. The protein sequence contains a potential metalloprotease motif (HEXPHEXGD), which fits the consensus sequence for the catalytic zinc-binding site motif of the zincin metalloproteases. This motif has identified a new subfamily of ZIP (Zrt-, Irt-like proteins) zinc transporters, which we have termed LZT (LIV-1 subfamily of ZIP zinc transporters). Expression of recombinant LIV-1 in Chinese-hamster ovary cells confirmed the prediction that LZT proteins can act as zinc-influx transporters. Zinc is essential for growth and zinc transporters have an important role in maintaining intracellular zinc homoeostasis, aberrations of which could lead to diseases such as cancer. This is the first report of the expression of a recombinant human LZT protein in mammalian cells. Recombinant LIV-1 locates to the plasma membrane, concentrated in lamellipodiae, similar to membrane-type metalloproteases. Examination of LIV-1 tissue expression located it mainly to hormonally controlled tissues with widespread expression in the brain. Interestingly, the LIV-1 sequence contains a strong PEST site and other potential degradation motifs, which, combined with our evidence that recombinant LIV-1 associates with ubiquitin, may explain the low-level expression of LIV-1. Combining the crucial role that zinc plays in cell growth and the proven role of metalloproteases in metastasis presents an exciting indication of how LIV-1 plays a role in breast cancer progression.

scholarly journals IL-17–CXC Chemokine Receptor 2 Axis Facilitates Breast Cancer Progression by Up-Regulating Neutrophil Recruitment

2020 ◽  
Vol 190 (1) ◽  
pp. 222-233 ◽  
Author(s):  
Lingyun Wu ◽  
Mohammad Awaji ◽  
Sugandha Saxena ◽  
Michelle L. Varney ◽  
Bhawna Sharma ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Chemokine Receptor ◽  
Neutrophil Recruitment ◽  
Breast Cancer Progression ◽  
Cxc Chemokine

scholarly journals PTEN and Other PtdIns(3,4,5)P3 Lipid Phosphatases in Breast Cancer

2020 ◽  
Vol 21 (23) ◽  
pp. 9189
Author(s):  
Mariah P. Csolle ◽  
Lisa M. Ooms ◽  
Antonella Papa ◽  
Christina A. Mitchell
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Invasive Disease ◽  
Breast Cancers ◽  
Inositol Polyphosphate ◽  
Akt Phosphorylation ◽  
Lipid Phosphatases ◽  
And Migration ◽  
Phosphoinositide 3 Kinase

The phosphoinositide 3-kinase (PI3K)/AKT signalling pathway is hyperactivated in ~70% of breast cancers. Class I PI3K generates PtdIns(3,4,5)P3 at the plasma membrane in response to growth factor stimulation, leading to AKT activation to drive cell proliferation, survival and migration. PTEN negatively regulates PI3K/AKT signalling by dephosphorylating PtdIns(3,4,5)P3 to form PtdIns(4,5)P2. PtdIns(3,4,5)P3 can also be hydrolysed by the inositol polyphosphate 5-phosphatases (5-phosphatases) to produce PtdIns(3,4)P2. Interestingly, while PTEN is a bona fide tumour suppressor and is frequently mutated/lost in breast cancer, 5-phosphatases such as PIPP, SHIP2 and SYNJ2, have demonstrated more diverse roles in regulating mammary tumourigenesis. Reduced PIPP expression is associated with triple negative breast cancers and reduced relapse-free and overall survival. Although PIPP depletion enhances AKT phosphorylation and supports tumour growth, this also inhibits cell migration and metastasis in vivo, in a breast cancer oncogene-driven murine model. Paradoxically, SHIP2 and SYNJ2 are increased in primary breast tumours, which correlates with invasive disease and reduced survival. SHIP2 or SYNJ2 overexpression promotes breast tumourigenesis via AKT-dependent and independent mechanisms. This review will discuss how PTEN, PIPP, SHIP2 and SYNJ2 distinctly regulate multiple functional targets, and the mechanisms by which dysregulation of these distinct phosphoinositide phosphatases differentially affect breast cancer progression.

scholarly journals The Role of CCL21/CCR7 Chemokine Axis in Breast Cancer Progression

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 1036 ◽  
Author(s):  
Balsam Rizeq ◽  
Mohammed Imad Malki
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Chemokine Receptor ◽  
Chemokine Receptors ◽  
Cancer Metastasis ◽  
Cellular Proliferation ◽  
Inflammatory Diseases ◽  
Breast Cancer Metastasis ◽  
Breast Cancer Progression ◽  
Cellular Interactions

Breast cancer is a leading cause of cancer-related deaths worldwide, predominantly caused by metastasis. It is generally accepted that the pattern of breast cancer metastasis is largely determined by the interaction between the chemokine receptors on cancer cells and the chemokines expressed at the sites of metastatic disease. Chemokine receptors belong to the G-protein-coupled receptors (GPCRs) family that appear to be implicated in inflammatory diseases, tumor growth and metastasis. One of its members, C-C Chemokine receptor 7 (CCR7), binds chemokines CCL19 and CCL21, which are important for tissue homeostasis, immune surveillance and tumorigenesis. These receptors have been shown to induce the pathobiology of breast cancer due to their ability to induce cellular proliferation and migration upon the binding of the cognate chemokine receptors. The underlying signaling pathways and exact cellular interactions within this biological system are not fully understood and need further insights. Thus, in this review, we summarize the essential roles of CCR7 and its receptors in breast cancer progression. Furthermore, we discuss the mechanisms of regulation that may lead to novel opportunities for therapeutic intervention. Despite the enormous advances in our knowledge of the nature of the chemokines in breast cancer metastasis, research about the involvement of CCR7 in cancer progression is still limited. Therefore, further studies are essential to illustrate the distinct roles of CCR7 in cancer progression and validate its potential as a preventive bio-factor for human breast cancer metastasis by targeting chemokine receptor genes.

scholarly journals CC Chemokine Receptor 5: The Interface of Host Immunity and Cancer

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Carlos Eduardo Coral de Oliveira ◽  
Julie Massayo Maeda Oda ◽  
Roberta Losi Guembarovski ◽  
Karen Brajão de Oliveira ◽  
Carolina Batista Ariza ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Cancer Progression ◽  
Chemokine Receptor ◽  
Malignant Tumors ◽  
Host Immunity ◽  
Immune Defense ◽  
Cellular Migration ◽  
Ccr5 Chemokine Receptor ◽  
Stromal Microenvironment ◽  
Promote Tumor Growth

Solid tumors are embedded in a stromal microenvironment consisting of immune cells, such as macrophages and lymphocytes, as well as nonimmune cells, such as endothelial cells and fibroblasts. Chemokines are a type of small secreted chemotactic cytokine and together with their receptors play key roles in the immune defense. Critically, they regulate cancer cellular migration and also contribute to their proliferation and survival. The CCR5 chemokine receptor is involved in leucocytes chemotaxis to sites of inflammation and plays an important role in the macrophages, T cells, and monocytes recruitment. Additionally, CCR5 may have an indirect effect on cancer progression by controlling the antitumor immune response, since it has been demonstrated that its expression could promote tumor growth and contribute to tumor metastasis, in different types of malignant tumors. Furthermore, it was demonstrated that a CCR5 antagonist may inhibit tumor growth, consisting of a possible therapeutic target. In this context, the present review focuses on the establishment of CCR5 within the interface of host immunity, tumor microenvironment, and its potential as a targeting to immunotherapy.

scholarly journals Hypoxia-Induced MALAT1 Promotes the Proliferation and Migration of Breast Cancer Cells by Sponging MiR-3064-5p

2021 ◽  
Vol 11 ◽  
Author(s):  
Chung-Hsien Shih ◽  
Li-Ling Chuang ◽  
Mong-Hsun Tsai ◽  
Li-Han Chen ◽  
Eric Y. Chuang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Breast Cancer Cells ◽  
Cellular Migration ◽  
Expression Levels ◽  
Promote Tumor Growth ◽  
Rna Immunoprecipitation ◽  
And Migration

Hypoxia, a common process during tumor growth, can lead to tumor aggressiveness and is tightly associated with poor prognosis. Long noncoding RNAs (lncRNAs) are long ribonucleotides (&gt;200 bases) with limited ability to translate proteins, and are known to affect many aspects of cellular function. One of their regulatory mechanisms is to function as a sponge for microRNA (miRNA) to modulate its biological functions. Previously, MALAT1 was identified as a hypoxia-induced lncRNA. However, the regulatory mechanism and functions of MALAT1 in breast cancer are still unclear. Therefore, we explored whether MALAT1 can regulate the functions of breast cancer cells through miRNAs. Our results showed the expression levels of MALAT1 were significantly up-regulated under hypoxia and regulated by HIF-1α and HIF-2α. Next, in contrast to previous reports, nuclear and cytoplasmic fractionation assays and fluorescence in situ hybridization indicated that MALAT1 was mainly located in the cytoplasm. Therefore, the labeling of MALAT1 as a nuclear marker should be done with the caveat. Furthermore, expression levels of miRNAs and RNA immunoprecipitation using antibody against AGO2 showed that MALAT1 functioned as a sponge of miRNA miR-3064-5p. Lastly, functional assays revealed that MALAT1 could promote cellular migration and proliferation of breast cancer cells. Our findings provide evidence that hypoxia-responsive long non-coding MALAT1 could be transcriptionally activated by HIF-1α and HIF-2α, act as a miRNA sponge of miR-3064-5p, and promote tumor growth and migration in breast cancer cells. These data suggest that MALAT1 may be a candidate for therapeutic targeting of breast cancer progression.

scholarly journals Conditional knockdown of integrin beta-3 reveals its involvement in osteolytic and soft tissue lesions of breast cancer skeletal metastasis

2020 ◽  
Author(s):  
Marineta Kovacheva ◽  
Michael Zepp ◽  
Stefan Berger ◽  
Martin R. Berger
Keyword(s):  
Breast Cancer ◽  
Soft Tissue ◽  
Cancer Progression ◽  
Cellular Proliferation ◽  
Skeletal Metastasis ◽  
Cellular Migration ◽  
Skeletal Metastases ◽  
The Impact

Abstract Integrin β3 (ITGB3) is probably related to skeletal metastasis, which is the most frequent complication in breast cancer progression. We aimed to define its role and suitability as target for anti-metastatic therapy. We generated two MDA-MB-231 cell clones with conditional miRNA-mediated ITGB3 knockdown for analyzing the resulting effects in vitro regarding mRNA expression, proliferation and migration, as well the impact on skeletal metastasis in a nude rat model. Furthermore, ITGB3 levels were analyzed in exosomes from plasma of rats with skeletal metastases, and from MDA-MB-231 cells incubated with these vesicles, as well as from exosomes secreted by cells with conditional ITGB3 knockdown. This inhibition of ITGB3 expression decreased cellular proliferation and more distinctly inhibited cellular migration. Reduction and even complete remissions of respective soft tissue and osteolytic lesions were detected after ITGB3 knockdown in vivo. Furthermore, ITGB3 levels were increased in exosomes isolated from plasma of rats harboring MDA-MB-231 lesions as well as in respective cells incubated with these vesicles in vitro. ITGB3 was distinctly decreased in exosomes from cells with ITGB3 knockdown. The observed in vitro and in vivo anti-ITGB3 effects can be explained by downregulation of specific genes, which have roles in angiogenesis (NPTN, RRM2), tumor growth (NPTN), energy metabolism (ISCA1), cytokinesis (SEPT11), migration (RRM2, STX6), cell proliferation, invasiveness, senescence, tumorigenesis (RRM2) and vesicle trafficking (SEPT11, STX6). ITGB3 has a role in breast cancer skeletal metastasis via gene expression modulation, as mirrored for ITGB3 in exosomes, thus it could serve as target for anti-metastatic therapy.

Beta haemoglobin (hbb) is a novel marker of breast cancer progression

2014 ◽  
Author(s):  
Mattia Capulli ◽  
Adriano Angelucci ◽  
Anna Teti ◽  
Patrizia Sanita ◽  
Luca Ventura ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Breast Cancer Progression
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