scholarly journals Curcumae Radix Extract Decreases Mammary Tumor-Derived Lung Metastasis via Suppression of C-C Chemokine Receptor Type 7 Expression

Nutrients ◽  
2019 ◽  
Vol 11 (2) ◽  
pp. 410 ◽  
Author(s):  
Pelin Kaya ◽  
Sang Lee ◽  
Young Lee ◽  
Sun Kwon ◽  
Hyun Yang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Lung Metastasis ◽  
Mammary Tumor ◽  
Chemokine Receptor ◽  
Cancer Metastasis ◽  
Breast Cancer Metastasis ◽  
Receptor Type ◽  
Primary Breast Tumor ◽  
Mcf7 Cells ◽  
Metastatic Activity

Curcumae radix is the dry root of Curcuma longa L. (turmeric) that can be used either as a spice or traditional medicine. The aim of this study was to investigate the survival benefits and the anti-metastatic activity of curcumae radix extract (CRE) in MCF7 cells and in MMTV-PyMT transgenic mice—a mouse model of breast cancer metastasis. In vitro wound scratch assay revealed that CRE treatment inhibited cell motility and cell migration in a dose-dependent manner. To investigate the effect of CRE in breast cancer metastasis, MMTV-PyMT transgenic female virgin mice were used and randomly divided into two groups. For survival curve analysis, CRE was administered in a dose of 50 mg/kg to 8–20-week-old mice. Interestingly, CRE treatment significantly increased the median and prolonged survival of MMTV-PyMT mice. Furthermore, CRE treatment decreased tumor burden and inhibited cell proliferation in primary breast tumor, and also suppressed mammary tumor-derived lung metastasis. The size of the lung metastases substantially decreased in the CRE-treated group compared with the ones in the control group. Curcumae radix extract showed anti-metastatic activity through regulating the expression of metastasis markers including C-C Chemokine Receptor Type 7, Matrix Metalloproteinase 9 and the proto-oncogenes c-fos and c-jun. We demonstrated that these metastatic regulators were decreased when CCR7 expression was suppressed in MCF7 cells transfected with CCR7 siRNA. The results of this study show that curcumae radix exerts antitumor and anti-metastatic activities, and we suggest that curcumae radix might be a potential supplement for the treatment and prevention of breast cancer metastasis.

scholarly journals The CXCR4-Dependent LASP1-Ago2 Interaction in Triple-Negative Breast Cancer

Cancers ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2455
Author(s):  
Augustus M. C. Tilley ◽  
Cory M. Howard ◽  
Sangita Sridharan ◽  
Boopathi Subramaniyan ◽  
Nicole R. Bearss ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Chemokine Receptor ◽  
Cancer Metastasis ◽  
Triple Negative ◽  
Receptor Type ◽  
Proximity Ligation Assay ◽  
Dependent Manner ◽  
Invasive Ability ◽  
Matrigel Invasion

The CXCR4-LASP1 axis is an emerging target in the field of breast cancer metastasis. C-X-C chemokine receptor type 4 (CXCR4) mediates directed cell migration when activated by its cognate ligand CXCL12. LIM and SH3 Protein 1 (LASP1) is a critical node in the CXCR4 signaling pathway, as its deficiency blocks CXCR4-dependent Matrigel invasion. The mechanism by which LASP1 facilitates this invasive ability of tumor cells when CXCR4 is activated is unknown. Our previous proteomics work had revealed several components of the RNA interference (RNAi) machinery as being potential LASP1 interacting proteins. Here we report that argonaute 2 (Ago2), a protein with central involvement in RNAi, associates with LASP1 in triple-negative breast cancer (TNBC) cells. We demonstrate that LASP1 co-immunoprecipitates with Ago2 endogenously in a CXCL12-dependent manner, with further confirmation of this interaction by proximity ligation assay. Furthermore, this association is specific to CXCR4 as it can be abrogated by the CXCR4 antagonist, AMD3465. By GST-pulldown approach, we identify that LASP1 directly binds to Ago2 through its LIM and SH3 domains, and that this binding is dictated by the S146 and Y171 phosphorylation sites of LASP1. Additionally, the phosphorylation status of LASP1 affected tumor suppressor microRNA (miRNA) Let-7a-guided Ago2 activity. Levels of several endogenous targets of Let-7a were found to be altered including C-C chemokine receptor type 7 (CCR7), which is another critical chemokine receptor involved in metastasis to lymph nodes. Our results suggest a novel role for the LASP1-Ago2 module in shaping the RNAi landscape, functionally impacting the invasive ability of cancer cells.

scholarly journals Involvement of Insulin Receptor Substrate 2 in Mammary Tumor Metastasis

2004 ◽  
Vol 24 (22) ◽  
pp. 9726-9735 ◽  
Author(s):  
Julie A. Nagle ◽  
Zhefu Ma ◽  
Maura A. Byrne ◽  
Morris F. White ◽  
Leslie M. Shaw
Keyword(s):  
Breast Cancer ◽  
Insulin Receptor ◽  
Tumor Cells ◽  
Mammary Tumor ◽  
Cancer Metastasis ◽  
Breast Cancer Metastasis ◽  
T Antigen ◽  
Insulin Receptor Substrate ◽  
Mammary Tumor Cells

ABSTRACT The insulin receptor substrate (IRS) proteins are adaptor molecules that integrate signals generated by receptors that are implicated in human breast cancer. We investigated the specific contribution of IRS-2 to mammary tumor progression using transgenic mice that express the polyoma virus middle T antigen (PyV-MT) in the mammary gland and IRS-2-null (IRS-2−/−) mice. PyV-MT-induced tumor initiation and growth were similar in wild-type (WT) and IRS-2−/− mice. However, the latency and incidence of metastasis were significantly decreased in the absence of IRS-2 expression. The contribution of IRS-2 to metastasis is intrinsic to the tumor cells, because IRS-2−/− mammary tumor cells did not metastasize when grown orthotopically in the mammary fat pads of WT mice. WT and IRS-2−/− tumors contained similar numbers of mitotic cells, but IRS-2−/− tumors had a higher incidence of apoptosis than did WT tumors. In vitro, IRS-2−/− mammary tumor cells were less invasive and more apoptotic in response to growth factor deprivation than their WT counterparts. In contrast, IRS-1−/− tumor cells, which express only IRS-2, were highly invasive and were resistant to apoptotic stimuli. Collectively, our findings reveal an important contribution of IRS-2 to breast cancer metastasis.

scholarly journals The AIB1 Oncogene Promotes Breast Cancer Metastasis by Activation of PEA3-Mediated Matrix Metalloproteinase 2 (MMP2) and MMP9 Expression

2008 ◽  
Vol 28 (19) ◽  
pp. 5937-5950 ◽  
Author(s):  
Li Qin ◽  
Lan Liao ◽  
Aisling Redmond ◽  
Leonie Young ◽  
Yuhui Yuan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Matrix Metalloproteinase ◽  
Tumor Cells ◽  
Lung Metastasis ◽  
Cancer Metastasis ◽  
Three Dimensional ◽  
Mammary Tumorigenesis ◽  
Breast Cancer Metastasis ◽  
Matrix Metalloproteinase 2 ◽  
Human Breast

ABSTRACT Amplified-in-breast cancer 1 (AIB1) is an overexpressed transcriptional coactivator in breast cancer. Although overproduced AIB1 is oncogenic, its role and underlying mechanisms in metastasis remain unclear. Here, mammary tumorigenesis and lung metastasis were investigated in wild-type (WT) and AIB1−/− mice harboring the mouse mammary tumor virus-polyomavirus middle T (PyMT) transgene. All WT/PyMT mice developed massive lung metastasis, but AIB1−/−/PyMT mice with comparable mammary tumors had significantly less lung metastasis. The recipient mice with transplanted AIB1−/−/PyMT tumors also had much less lung metastasis than the recipient mice with transplanted WT/PyMT tumors. WT/PyMT tumor cells expressed mesenchymal markers such as vimentin and N-cadherin, migrated and invaded rapidly, and formed disorganized cellular masses in three-dimensional cultures. In contrast, AIB1−/−/PyMT tumor cells maintained epithelial markers such as E-cadherin and ZO-1, migrated and invaded slowly, and still formed polarized acinar structures in three-dimensional cultures. Molecular analyses revealed that AIB1 served as a PEA3 coactivator and formed complexes with PEA3 on matrix metalloproteinase 2 (MMP2) and MMP9 promoters to enhance their expression in both mouse and human breast cancer cells. In 560 human breast tumors, AIB1 expression was found to be positively associated with PEA3, MMP2, and MMP9. These findings suggest a new alternative strategy for controlling the deleterious roles of these MMPs in breast cancer by inhibiting their upstream coregulator AIB1.

scholarly journals Aiduqing formula inhibits breast cancer metastasis by suppressing TAM/CXCL1-induced Treg differentiation and infiltration

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Jing Li ◽  
Shengqi Wang ◽  
Neng Wang ◽  
Yifeng Zheng ◽  
Bowen Yang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Flow Cytometry ◽  
T Cells ◽  
Lung Metastasis ◽  
Molecular Mechanisms ◽  
Cancer Metastasis ◽  
Breast Cancer Metastasis ◽  
Luciferase Reporter ◽  
Immune Balance ◽  
Gene Assay

Abstract Background Metastasis represents the leading cause of death in patients with breast cancer. Traditional Chinese medicine is particularly appreciated for metastatic diseases in Asian countries due to its benefits for survival period prolongation and immune balance modulation. However, the underlying molecular mechanisms remain largely unknown. This study aimed to explore the antimetastatic effect and immunomodulatory function of a clinical formula Aiduqing (ADQ). Methods Naive CD4+ T cells, regulatory T cells (Tregs), and CD8+ T cells were sorted by flow cytometry. Then, breast cancer cells and these immune cells were co-cultured in vitro or co-injected into mice in vivo to simulate their coexistence. Flow cytometry, ELISA, qPCR, double luciferase reporter gene assay, and chromatin immunoprecipitation assay were conducted to investigate the immunomodulatory and antimetastatic mechanisms of ADQ. Results ADQ treatment by oral gavage significantly suppressed 4T1-Luc xenograft growth and lung metastasis in the orthotopic breast cancer mouse model, without noticeable hepatotoxicity, nephrotoxicity, or hematotoxicity. Meanwhile, ADQ remodeled the immunosuppressive tumor microenvironment (TME) by increasing the infiltration of tumor-infiltrating lymphocytes (TILs) and cytotoxic CD8+ T cells, and decreasing the infiltration of Tregs, naive CD4+ T cells, and tumor-associated macrophages (TAMs). Molecular mechanism studies revealed that ADQ remarkably inhibited CXCL1 expression and secretion from TAMs and thus suppressed the chemotaxis and differentiation of naive CD4+ T cells into Tregs, leading to the enhanced cytotoxic effects of CD8+ T cells. Mechanistically, TAM-derived CXCL1 promoted the differentiation of naive CD4+ T cells into Tregs by transcriptionally activating the NF-κB/FOXP3 signaling. Lastly, mouse 4T1-Luc xenograft experiments validated that ADQ formula inhibited breast cancer immune escape and lung metastasis by suppressing the TAM/CXCL1/Treg pathway. Conclusions This study not only provides preclinical evidence supporting the application of ADQ in inhibiting breast cancer metastasis but also sheds novel insights into TAM/CXCL1/NF-κB/FOXP3 signaling as a promising therapeutic target for Treg modulation and breast cancer immunotherapy.

The improved targeting of an aspirin prodrug albumin-based nanosystem for visualizing and inhibiting lung metastasis of breast cancer

2020 ◽  
Vol 8 (21) ◽  
pp. 5941-5954
Author(s):  
Wancun Zhang ◽  
Lili Xia ◽  
Xiangyu Ren ◽  
Mengyuan Cui ◽  
Tianguang Liu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Lung Metastasis ◽  
Cancer Metastasis ◽  
Breast Cancer Metastasis

The nanoplatform FA-BSA@DA was developed for the loading of the aspirin prodrug DA and for the subsequent visualization and inhibition of breast cancer metastasis to the lung.

scholarly journals Dexamethasone enhances the lung metastasis of breast cancer via a PI3K-SGK1-CTGF pathway

Oncogene ◽  
2021 ◽  
Author(s):  
Yujing Zhang ◽  
Gang Shi ◽  
Hantao Zhang ◽  
Qi Xiong ◽  
Fuyi Cheng ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Treatment ◽  
Tumor Cells ◽  
Breast Cancer Cell ◽  
Lung Metastasis ◽  
Cancer Metastasis ◽  
Breast Cancer Metastasis ◽  
Breast Cancer Treatment

AbstractDexamethasone (Dex), as a pretreatment agent, is widely used to attenuate the side effects of chemotherapy in breast cancer treatment. However, whether and how Dex affects breast cancer metastasis remain to be furtherly understood. In this study, we established several mouse breast cancer metastatic models to study the effect of Dex in vitro and in vivo. Transwell, Western Blot and RNA interference were applied to study the molecular mechanism of Dex in promoting breast cancer cell migration. Meanwhile, the effect of Dex on lung metastasis of breast cancer in Dex combined with PTX chemotherapy was discussed. Our results confirmed that Dex could promote breast cancer cell metastasis both in vitro and in vivo. Mechanistic studies revealed that this pro-metastatic effect of Dex was mediated by the GR-PI3K-SGK1-CTGF pathway in tumor cells. Ligation of Dex and glucocorticoid receptor (GR) on tumor cells activated the PI3K signaling pathway and upregulated serum glucocorticoid-inducible kinase 1 (SGK1) expression, and then increased the expression of connective tissue growth factor (CTGF) through Nedd4l-Smad2. Moreover, Dex was the leading factor for lung metastasis in a standard regimen for breast cancer treatment with paclitaxel and Dex. Importantly, targeting SGK1 with the inhibitor GSK650394 remarkably reduced lung metastasis in this regimen. Our present data provide new insights into Dex-induced breast cancer metastasis and indicate that SGK1 could be a candidate target for the treatment of breast cancer metastasis.

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 USP12 promotes breast cancer angiogenesis by maintaining midkine stability

2021 ◽  
Vol 12 (11) ◽  
Author(s):  
Bin Sheng ◽  
Zichao Wei ◽  
Xiaowei Wu ◽  
Yi Li ◽  
Zhihua Liu
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Lung Metastasis ◽  
Breast Cancer Cells ◽  
Cancer Metastasis ◽  
Umbilical Vein ◽  
Breast Cancer Metastasis ◽  
Mouse Lung ◽  
Breast Cancer Patients

AbstractDeubiquitinases (DUBs) have important biological functions, but their roles in breast cancer metastasis are not completely clear. In this study, through screening a series of DUBs related to breast cancer distant metastasis-free survival (DMFS) in the Kaplan-Meier Plotter database, we identified ubiquitin-specific protease 12 (USP12) as a key deubiquitinating enzyme for breast cancer metastasis. We confirmed this via an orthotopic mouse lung metastasis model. We revealed that the DMFS of breast cancer patients with high USP12 was worse than that of others. Knockdown of USP12 decreased the lung metastasis ability of 4T1 cells, while USP12 overexpression increased the lung metastasis ability of these cells in vivo. Furthermore, our results showed that the supernatant from USP12-overexpressing breast cancer cells could promote angiogenesis according to human umbilical vein endothelial cell (HUVEC) migration and tube formation assays. Subsequently, we identified midkine (MDK) as one of its substrates. USP12 could directly interact with MDK, decrease its polyubiquitination and increase its protein stability in cells. Overexpression of MDK rescued the loss of angiogenesis ability mediated by knockdown of USP12 in breast cancer cells in vitro and in vivo. There was a strong positive relationship between USP12 and MDK protein expression in clinical breast cancer samples. Consistent with the pattern for USP12, high MDK expression predicted lower DMFS and overall survival (OS) in breast cancer. Collectively, our study identified that USP12 is responsible for deubiquitinating and stabilizing MDK and leads to metastasis by promoting angiogenesis. Therefore, the USP12–MDK axis could serve as a potential target for the therapeutic treatment of breast cancer metastasis.

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