scholarly journals MDM2 Promotes Cell Motility and Invasiveness by Regulating E-Cadherin Degradation

2006 ◽  
Vol 26 (19) ◽  
pp. 7269-7282 ◽  
Author(s):  
Jer-Yen Yang ◽  
Cong S. Zong ◽  
Weiya Xia ◽  
Yongkun Wei ◽  
Mohamed Ali-Seyed ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Motility ◽  
Cancer Metastasis ◽  
Ectopic Expression ◽  
Dominant Negative ◽  
Antibody Array ◽  
Breast Cancer Patients ◽  
Mdm2 Gene ◽  
E Cadherin

ABSTRACT Gene amplification and protein overexpression of MDM2, which is often found in certain types of cancers, indicate that MDM2 plays an important role in tumorigenesis. Interestingly, several clinical reports have demonstrated that amplification of the MDM2 gene correlates with the metastatic stage. Using an antibody array assay, we identified E-cadherin as an MDM2-binding protein and confirmed that E-cadherin is a substrate for the MDM2 E3 ubiquitin ligase. We demonstrate that MDM2 interacts in vivo with E-cadherin, resulting in its ubiquitination and degradation. This regulation appears to be clinically relevant, as we found a significant correlation between high MDM2 and low E-cadherin protein levels in resected tumor specimens recovered from breast cancer patients with lymph node metastases. Ectopic expression of MDM2 in breast cancer cells was found to disrupt cell-cell contacts and enhance cell motility and invasive potential. We found that E-cadherin and MDM2 colocalized on the plasma membrane and in the early endosome, where ubiquitin moieties were attached to E-cadherin. Blocking endocytosis with dominant-negative mutants of dynamin abolished the association of MDM2 with E-cadherin, prevented E-cadherin degradation, and attenuated cell motility as observed by fluorescence microscopy. Thus, we provide evidence to support a novel role for MDM2 in regulating cell adhesions by a mechanism that involves degrading and down-regulating the expression of E-cadherin via an endosome pathway. This novel MDM2-regulated pathway is likely to play a biologically relevant role in cancer metastasis.

scholarly journals FOXO3a-driven miRNA signatures suppresses VEGF-A/NRP1 signaling and breast cancer metastasis

Oncogene ◽  
2020 ◽  
Author(s):  
Ying Song ◽  
Shanshan Zeng ◽  
Guopei Zheng ◽  
Danyang Chen ◽  
Pan Li ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Transcription Factor ◽  
Cancer Metastasis ◽  
Critical Role ◽  
Ectopic Expression ◽  
Breast Cancer Metastasis ◽  
Metastasis Suppressor ◽  
Breast Cancer Patients ◽  
Signaling Axis

AbstractMetastasis remains the major obstacle to improved survival for breast cancer patients. Downregulation of FOXO3a transcription factor in breast cancer is causally associated with the development of metastasis through poorly understood mechanisms. Here, we report that FOXO3a is functionally related to the inhibition of VEGF-A/NRP1 signaling and to the consequent suppression of breast cancer metastasis. We show that FOXO3a directly induces miR-29b-2 and miR-338 expression. Ectopic expression of miR-29b-2/miR-338 significantly suppresses EMT, migration/invasion, and in vivo metastasis of breast cancer. Moreover, we demonstrate that miR-29b-2 directly targets VEGF-A while miR-338 directly targets NRP1, and show that regulation of miR-29b-2 and miR-338 mediates the ability of FOXO3a to suppress VEGF-A/NRP1 signaling and breast cancer metastasis. Clinically, our results show that the FOXO3a-miR-29b-2/miR-338-VEGF-A/NRP1 axis is dysregulated and plays a critical role in disease progression in breast cancer. Collectively, our findings propose that FOXO3a functions as a metastasis suppressor, and define a novel signaling axis of FOXO3a-miRNA-VEGF-A/NRP1 in breast cancer, which might be potential therapeutic targets for breast cancer.

Serum ANGPTL2 Levels Reflect Clinical Features of Breast Cancer Patients: Implications for the Pathogenesis of Breast Cancer Metastasis

2014 ◽  
Vol 29 (3) ◽  
pp. 239-245 ◽  
Author(s):  
Motoyoshi Endo ◽  
Yutaka Yamamoto ◽  
Masahiro Nakano ◽  
Tetsuro Masuda ◽  
Haruki Odagiri ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Clinical Features ◽  
Cancer Progression ◽  
Breast Cancer Cells ◽  
Cancer Metastasis ◽  
Ductal Carcinoma ◽  
Breast Cancer Metastasis ◽  
Breast Cancer Patients

Introduction Breast cancer is a leading cause of cancer-related death in women worldwide, and its metastasis is a major cause of disease mortality. Therefore, identification of the mechanisms underlying breast cancer metastasis is crucial for the development of therapeutic and diagnostic strategies. Our recent study of immunodeficient female mice transplanted with MDA-MB231 breast cancer cells demonstrated that tumor cell-derived angiopoietin-like protein 2 (ANGPTL2) accelerates metastasis through both increasing tumor cell migration in an autocrine/paracrine manner, and enhancing tumor angiogenesis. To determine whether ANGPTL2 contributes to its clinical pathogenesis, we asked whether serum ANGPTL2 levels reflect the clinical features of breast cancer progression. Methods We monitored the levels of secreted ANGPTL2 in supernatants of cultured proliferating MDA-MB231 cells. We also determined whether the circulating ANGPTL2 levels were positively correlated with cancer progression in an in vivo breast cancer xenograft model using MDA-MB231 cells. Finally, we investigated whether serum ANGPTL2 levels were associated with clinical features in breast cancer patients. Results Both in vitro and in vivo experiments showed that the levels of ANGPTL2 secreted from breast cancer cells increased with cell proliferation and cancer progression. Serum ANGPTL2 levels in patients with metastatic breast cancer were significantly higher than those in healthy subjects or in patients with ductal carcinoma in situ or non-metastatic invasive ductal carcinoma. Serum ANGPTL2 levels in patients negative for estrogen receptors and progesterone receptors, particularly triple-negative cases, reflected histological grades. Conclusions These findings suggest that serum ANGPTL2 levels in breast cancer patients could represent a potential marker of breast cancer metastasis.

scholarly journals The Wnt-5a–Derived Hexapeptide Foxy-5 Inhibits Breast Cancer Metastasis In vivo by Targeting Cell Motility

2008 ◽  
Vol 14 (20) ◽  
pp. 6556-6563 ◽  
Author(s):  
Annette Säfholm ◽  
Johanna Tuomela ◽  
Jeanette Rosenkvist ◽  
Janna Dejmek ◽  
Pirkko Härkönen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Motility ◽  
Cancer Metastasis ◽  
Breast Cancer Metastasis

scholarly journals ZMYND10, an epigenetically regulated tumor suppressor, exerts tumor-suppressive functions via miR145-5p/NEDD9 axis in breast cancer

2019 ◽  
Vol 11 (1) ◽  
Author(s):  
Yan Wang ◽  
Liangying Dan ◽  
Qianqian Li ◽  
Lili Li ◽  
Lan Zhong ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Suppressor ◽  
Signaling Pathway ◽  
Cancer Metastasis ◽  
Ectopic Expression ◽  
Migration And Invasion ◽  
Breast Cancer Cell Lines ◽  
Multiple Tumor

Abstract Background Recent studies suggested that ZMYND10 is a potential tumor suppressor gene in multiple tumor types. However, the mechanism by which ZMYND10 inhibits breast cancer remains unclear. Here, we investigated the role and mechanism of ZMYND10 in breast cancer inhibition. Results ZMYND10 was dramatically reduced in multiple breast cancer cell lines and tissues, which was associated with promoter hypermethylation. Ectopic expression of ZMYND10 in silenced breast cancer cells induced cell apoptosis while suppressed cell growth, cell migration and invasion in vitro, and xenograft tumor growth in vivo. Furthermore, molecular mechanism studies indicated that ZMYND10 enhances expression of miR145-5p, which suppresses the expression of NEDD9 protein through directly targeting the 3'-untranslated region of NEDD9 mRNA. Conclusions Results from this study show that ZMYND10 suppresses breast cancer tumorigenicity by inhibiting the miR145-5p/NEDD9 signaling pathway. This novel discovered signaling pathway may be a valid target for small molecules that might help to develop new therapies to better inhibit the breast cancer metastasis.

scholarly journals Ral GTPases promote breast cancer metastasis by controlling biogenesis and organ targeting of exosomes

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Shima Ghoroghi ◽  
Benjamin Mary ◽  
Annabel Larnicol ◽  
Nandini Asokan ◽  
Annick Klein ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Metastasis ◽  
Breast Cancer Metastasis ◽  
Dependent Manner ◽  
Breast Cancer Patients ◽  
Family Control ◽  
Ral Gtpases ◽  
Phospholipase D1 ◽  
Organ Targeting

Cancer extracellular vesicles (EVs) shuttle at distance and fertilize pre-metastatic niches facilitating subsequent seeding by tumor cells. However, the link between EV secretion mechanisms and their capacity to form pre-metastatic niches remains obscure. Using mouse models, we show that GTPases of the Ral family control, through the phospholipase D1, multi-vesicular bodies homeostasis and tune the biogenesis and secretion of pro-metastatic EVs. Importantly, EVs from RalA or RalB depleted cells have limited organotropic capacities in vivo and are less efficient in promoting metastasis. RalA and RalB reduce the EV levels of the adhesion molecule MCAM/CD146, which favors EV-mediated metastasis by allowing EVs targeting to the lungs. Finally, RalA, RalB and MCAM/CD146, are factors of poor prognosis in breast cancer patients. Altogether, our study identifies RalGTPases as central molecules linking the mechanisms of EVs secretion and cargo loading to their capacity to disseminate and induce pre-metastatic niches in a CD146 dependent manner.

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.

scholarly journals A novel long non-coding RNA AC073352.1 promotes metastasis and angiogenesis via interacting with YBX1 in breast cancer

2021 ◽  
Vol 12 (7) ◽  
Author(s):  
Xue Kong ◽  
Juan Li ◽  
Yanru Li ◽  
Weili Duan ◽  
Qiuchen Qi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Poor Prognosis ◽  
Breast Cancer Cells ◽  
Cancer Metastasis ◽  
Breast Cancer Metastasis ◽  
Migration And Invasion ◽  
Breast Cancer Patients

AbstractBreast cancer is the major cause of cancer death worldwide in women. Patients with metastasis have poor prognosis and the mechanisms of breast cancer metastasis are not completely understood. Long non-coding RNAs (lncRNAs) have been shown to have crucial roles in breast cancer development and progression. However, the underlying mechanisms by which lncRNA-driven breast cancer metastasis are unknown. The main objective of this paper is to explore a functional lncRNA and its mechanisms in breast cancer. Here we identified a novel lncRNA AC073352.1 that was significantly upregulated in breast cancer tissues and was associated with advanced TNM stages and poor prognosis in breast cancer patients. In addition, AC073352.1 was found to promote the migration and invasion of breast cancer cells in vitro and enhance breast cancer metastasis in vivo. Mechanistically, we elucidated that AC073352.1 interacted with YBX1 and stabilized its protein expression. Knock down of YBX1 reduced breast cancer cell migration and invasion and could partially reverse the stimulative effects of AC073352.1 overexpressed on breast cancer metastasis. Moreover, AC073352.1 might be packaged into exosomes by binding to YBX1 in breast cancer cells resulting in angiogenesis. Collectively, our results demonstrated that AC073352.1 promoted breast cancer metastasis and angiogenesis via binding YBX1, and it could serve as a promising, novel biomarker for prognosis and a therapeutic target in breast cancer.

scholarly journals Peran Matriks Metalloproteinase 8 Pada Metastasis Sel Kanker Payudara

2021 ◽  
Vol 1 (2) ◽  
pp. 31-35
Author(s):  
Mike Permata Sari
Keyword(s):  
Breast Cancer ◽  
Cancer Metastasis ◽  
Breast Cancer Metastasis ◽  
Normal Breast ◽  
Breast Cancer Patients ◽  
Direct Role ◽  
Stat3 Signaling Pathway ◽  
Extracellular Proteinases ◽  
Breast Cells ◽  
E Cadherin

MMP-8 merupakan protease yang diproduksi oleh neutrofil dan berperan dalam degradasi kolagen yang terdapat pada jaringan ikat pada mamalia. Pada manusia, protein MMP-8 disandi oleh gen MMP-8. Pada umumnya, MMP disekresi dalam bentuk proprotein yang diaktifkan ketika dipecah oleh proteinase ekstraseluler. Peningkatan Ekspresi MMP-8 berlebih pada penderita kanker payudara di fase yang berbeda, peningkatan ekspresi MMP-8 tidak ditemukan pada sel payudara normal. MMP-8 memiliki substrat yang berbeda dengan MMP-2 dan MMP-9 yang berperan langsung dalam penyebab metastasis sel kanker payudara ke organ lain. Peran MMP-8 terhadap kanker payudara telah dilaporkan oleh penelitian sebelumnya bahwa MMP-8 mampu memicu metastasis kanker payudara melalui peningkatan sitokin proinflamasi yaitu IL-6 dan IL-8.  IL-6 dan IL-8 menginduksi metastasis melalui jalur persinyalan JAK/STAT3 yang akan mengaktifkan snail/slug/twist yang akan menekan ekspresi E-cadherin, selain itu IL-6 dan IL-8 memicu sintesis VEGF sehingga mengakibatkan pembentukan pembuluh darah baru. MMP-8 is a protease produced by neutrophils and plays a role in the degradation of collagen found in connective tissue in mammals. In humans, the MMP-8 protein is encoded by the MMP-8 gene. In general, MMPs are secreted in the form of proproteins that are activated when cleaved by extracellular proteinases. MMP-8 Ekspression increased in breast cancer patients at different stages, but it is not happenin normal breast cells. MMP-8 has a different substrate with MMP-2 and MMP-9 which play a direct role in causing breast cancer cell metastasis to other organs. The role of MMP-8 in breast cancer has been reported by previous studies that MMP-8 is able to trigger breast cancer metastasis through an increase in proinflammatory cytokines,such as IL-6 and IL-8. IL-6 and IL-8 induce metastasis through the JAK/STAT3 signaling pathway which will activate snail/slug/twist which will suppress E-cadherin expression, in addition IL-6 and IL-8 trigger VEGF synthesis, resulting in the formation of new blood vessels.

scholarly journals Heregulin/ErbB3 Signaling Enhances CXCR4-Driven Rac1 Activation and Breast Cancer Cell Motility via Hypoxia-Inducible Factor 1α

2016 ◽  
Vol 36 (15) ◽  
pp. 2011-2026 ◽  
Author(s):  
Cynthia Lopez-Haber ◽  
Laura Barrio-Real ◽  
Victoria Casado-Medrano ◽  
Marcelo G. Kazanietz
Keyword(s):  
Breast Cancer ◽  
Cell Motility ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Cancer Metastasis ◽  
Hypoxia Inducible Factor ◽  
Nucleotide Exchange ◽  
Breast Cancer Patients ◽  
Cancer Cell Motility ◽  
Hypoxia Inducible Factor 1Α

The growth factor heregulin (HRG), a ligand of ErbB3 and ErbB4 receptors, contributes to breast cancer development and the promotion of metastatic disease, and its expression in breast tumors has been associated with poor clinical outcome and resistance to therapy. In this study, we found that breast cancer cells exposed to sustained HRG treatment show markedly enhanced Rac1 activation and migratory activity in response to the CXCR4 ligand SDF-1/CXCL12, effects mediated by P-Rex1, a Rac-guanine nucleotide exchange factor (GEF) aberrantly expressed in breast cancer. Notably, HRG treatment upregulates surface expression levels of CXCR4, a G protein-coupled receptor (GPCR) implicated in breast cancer metastasis and an indicator of poor prognosis in breast cancer patients. A detailed mechanistic analysis revealed that CXCR4 upregulation and sensitization of the Rac response/motility by HRG are mediated by the transcription factor hypoxia-inducible factor 1α (HIF-1α) via ErbB3 and independently of ErbB4. HRG caused prominent induction in the nuclear expression of HIF-1α, which transcriptionally activates theCXCR4gene via binding to a responsive element located in positions −1376 to −1372 in theCXCR4promoter, as revealed by mutagenesis analysis and chromatin immunoprecipitation (ChIP). Our results uncovered a novel function for ErbB3 in enhancing breast cancer cell motility and sensitization of the P-Rex1/Rac1 pathway through HIF-1α-mediated transcriptional induction of CXCR4.

scholarly journals Ruyiping formula inhibits metastasis via the microRNA-134-SLUG axis in breast cancer

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Ziwei Jiang ◽  
Lixia Pei ◽  
Ying Xie ◽  
Qun Ye ◽  
Xiaoqiang Liang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Cancer Metastasis ◽  
Breast Cancer Metastasis ◽  
Breast Cancer Patients ◽  
Tumor Expression

Abstract Background Metastasis is the leading cause of death among breast cancer patients. MicroRNA-134 has been reported to have a tumor-suppressive role in breast cancer. Ruyiping (RYP), a traditional Chinese formula, has been shown with the ability to reduce breast cancer metastasis in pre-clinical studies. This present study was designed to examine whether miR-134 was involved in RYP-inhibited breast cancer metastasis. Methods The expression of SLUG, E-Cadherin, N-Cadherin and miR-134 in MDA-MB-231 and 4 T1 cells treated with RYP or vehicle control were determined by quantitative realtime-PCR and western blot. Invasiveness determined by transwell assay as well as SLUG gene expression determined by qPCR were detected in cells transfected with chemically synthesized miR-134 mimics or inhibitors. BALB/c mice were injected with 4 T1 cells orthotopically and fed with RYP through gavage. Breast tumor growth, metastasis and tumor expression of EMT markers were detected. Results Compared with the control, Ruyiping formula significantly inhibited SLUG-regulated breast cancer cells invasion. MiR-134 was induced by RYP in vitro and in vivo and was able to suppress SLUG by targeting its 3’UTR. RYP suppressed SLUG expression and cell invasion through miR-134. In 4 T1 tumor-bearing mice, RYP significantly inhibited 4 T1 tumor growth and lung metastasis, increased the levels of miR-134 and epithelial marker while decreased the levels of SLUG and mesenchymal marker. Conclusion Our data uncovered that Ruyiping formula exerts an anti-metastatic activity against breast cancer cells by regulating SLUG through miR-134. MiR-134-SLUG axis might be a promising strategy in breast cancer therapy.

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