scholarly journals α-Arrestin ARRDC3 tumor suppressor function is linked to GPCR-induced TAZ activation and breast cancer metastasis

2021 ◽  
Vol 134 (8) ◽  
Author(s):  
Aleena K. S. Arakaki ◽  
Wen-An Pan ◽  
Helen Wedegaertner ◽  
Ivette Roca-Mercado ◽  
Logan Chinn ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Suppressor ◽  
Cancer Progression ◽  
Cancer Metastasis ◽  
Hippo Pathway ◽  
Breast Cancer Metastasis ◽  
Migration And Invasion ◽  
Hippo Signaling ◽  
The Hippo Pathway

ABSTRACT The α-arrestin domain containing protein 3 (ARRDC3) is a tumor suppressor in triple-negative breast carcinoma (TNBC), a highly metastatic subtype of breast cancer that lacks targeted therapies. Thus, understanding the mechanisms and targets of ARRDC3 in TNBC is important. ARRDC3 regulates trafficking of protease-activated receptor 1 (PAR1, also known as F2R), a G-protein-coupled receptor (GPCR) implicated in breast cancer metastasis. Loss of ARRDC3 causes overexpression of PAR1 and aberrant signaling. Moreover, dysregulation of GPCR-induced Hippo signaling is associated with breast cancer progression. However, the mechanisms responsible for Hippo dysregulation remain unknown. Here, we report that the Hippo pathway transcriptional co-activator TAZ (also known as WWTR1) is the major effector of GPCR signaling and is required for TNBC migration and invasion. Additionally, ARRDC3 suppresses PAR1-induced Hippo signaling via sequestration of TAZ, which occurs independently of ARRDC3-regulated PAR1 trafficking. The ARRDC3 C-terminal PPXY motifs and TAZ WW domain are crucial for this interaction and are required for suppression of TNBC migration and lung metastasis in vivo. These studies are the first to demonstrate a role for ARRDC3 in regulating GPCR-induced TAZ activity in TNBC and reveal multi-faceted tumor suppressor functions of ARRDC3. This article has an associated First Person interview with the first author of the paper.

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 NUPR1 Promotes the Proliferation and Migration of Breast Cancer Cells by Activating TFE3 Transcription to Induce Autophagy

2021 ◽  
Author(s):  
Heng Xiao ◽  
Jing Long ◽  
Xiang Chen ◽  
Mi-Duo Tan
Keyword(s):  
Breast Cancer ◽  
Western Blot ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Cancer Metastasis ◽  
Translocation Factor ◽  
Breast Cancer Metastasis ◽  
Migration And Invasion ◽  
Related Proteins

Abstract Background: Breast cancer is a commonplace carcinoma in females. Recurrence and metastasis are the main problems affecting the survival rate of patients. The fundamental reason is the lack of understanding of the mechanism of breast cancer metastasis. This study aims to deliberate on the efficaciousness of Nuclear protein 1 (NUPR1)-mediated autophagy on breast cancer metastasis.Methods: The proliferation, migration and invasion ability of breast cancer cells were appraised by CCK-8, wound healing, and colony formation, as well as transwell assay. The relationship between NUPR1 and Translocation factor E3 (TFE3) was appraised by qPCR, western blot and ChIP. Migration-invasion-related proteins and autophagy-related proteins were appraised by western blot. The effects of NUPR1 on malignancy formation and metastasis were studied in vivo.Results: NUPR1 was upregulated in breast cancer cells and tissues. NUPR1 knockdown restrained the proliferation, migration and invasion of ZR-75-30 cells. Moreover, NUPR1 knockdown restrained malignancy formation and metastasis in vivo. Mechanically, NUPR1 promoted autophagy through activation of TFE3 transcription, thereby regulating the process of breast cancer metastasis.Conclusion: This paper elucidates the molecular mechanism of NUPR1 promoting breast cancer metastasis by activating autophagy through TFE3 signaling pathway, which provided biological basis for intervention of blocking distant metastasis.

Realgar Nanoparticles Inhibit Migration, Invasion and Metastasis in a Mouse Model of Breast Cancer by Suppressing Matrix Metalloproteinases and Angiogenesis

2020 ◽  
Vol 17 (2) ◽  
pp. 148-158 ◽  
Author(s):  
Xi Xiaoxia ◽  
Sun Jing ◽  
Xi Dongbin ◽  
Tian Yonggang ◽  
Zhang Jingke ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Liver Cancer ◽  
Breast Cancer Cells ◽  
Cancer Metastasis ◽  
Breast Cancer Metastasis ◽  
Migration And Invasion ◽  
Invasion And Metastasis ◽  
Mouse Breast Cancer ◽  
Metastasis Model

Background: Realgar, a traditional Chinese medicine, has shown antitumor efficacy in several tumor types. We previously showed that realgar nanoparticles (nano-realgar) had significant antileukemia, anti-lung cancer and anti-liver cancer effects. In addition, the anti-tumor effects of nanorealgar were significantly better than those of ordinary realgar. Objective: To explore the inhibitory effects and molecular mechanisms of nano-realgar on the migration, invasion and metastasis of mouse breast cancer cells. Methods: Wound-healing migration assays and Transwell invasion assays were carried out to determine the effects of nano-realgar on breast cancer cell (4T1) migration and invasion. The expression levels of matrix metalloproteinase (MMP)-2 and -9 were measured by Western blot. A murine breast cancer metastasis model was established, administered nano-realgar for 32 days and monitored for tumor growth and metastasis by an in vivo optical imaging system. Finally, living imaging and hematoxylin and eosin (HE) staining were used to measure the morphology and pathology of lung and liver cancer cell metastases, respectively. Angiogenesis was assessed by CD34 immunohistochemistry. Results: Nano-realgar significantly inhibited the migration and invasion of breast cancer 4T1 cells and the expression of MMP-2 and -9. Meanwhile, nano-realgar effectively suppressed the abilities of tumor growth, metastasis and angiogenesis in the murine breast cancer metastasis model in a time- and dosedependent manner. Conclusion: Nano-realgar significantly inhibited migration and invasion of mouse breast cancer cells in vitro as well as pulmonary and hepatic metastasis in vivo, which may be closely correlated with the downexpression of MMP-2 and -9 and suppression of tumor neovascularization.

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.

Structural Maintenance of Chromosomes 1A (SMC1A) regulated by KIAA1429 in m6A-independent manner promotes EMT progress in breast cancer

2021 ◽  
Author(s):  
Xu Zhang ◽  
Xin-Yuan Dai ◽  
Jia-Yi Qian ◽  
Feng Xu ◽  
Zhang-Wei Wang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Cancer Metastasis ◽  
Breast Cancer Metastasis ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Western Blots ◽  
Potential Biomarker

Abstract Background As a component in the m6A ‘writers’, KIAA1429 was reported to promote breast cancer proliferation and growth in m6A-independent manners. However, the related mechanism of KIAA1429 in breast cancer metastasis have not been reported. Methods Western blots and quantitative real-time PCR were carried out to verify the expression of KIAA1429 in breast cancer cells SUM1315 and ZR-75-1 after KIAA1429 knockdown or overexpression. Transwell and in vivo metastasis assay were conducted to investigate the effects of KIAA1429 on migration and invasion of breast cancer cells. RIP and REMSA assay was performed to explore the direct correlation between KIAA1429 and SMC1A mRNA. ChIP assay combined with luciferase reporter assay were apply to explore the direct binding between SMC1A and SNAIL promotor region. Results KIAA1429 could significantly promote the migration and invasion of breast cancer cells. Knockdown of KIAA1429 could impede breast cancer metastasis in nude mice in vivo. The level of SNAIL expression and EMT progress was positively related with KIAA1429. Knockdown of KIAA1429 induced cell migration, invasion and EMT progress could be reversed by the upregulation of SNAIL. However, SMC1A, not KIAA1429 bound with SNAIL promoter region directly and promoted the transcription of SNAIL. Then, KIAA1429 could bind to the motif in the 3′-UTR of SMC1A mRNA directly and enhanced SMC1A mRNA stability. Conclusions In conclusion, our study revealed a novel mechanism of the KIAA1429/SMC1A/SNAIL axis in the regulation of invasion and metastasis of breast cancer, which may provide a potential biomarker and therapeutic target for breast cancer. Moreover, it firstly provided compelling evidences that KIAA1429 could regulate the targeted gene expression at posttranscriptional levels as an RNA-binding protein, unrelated the m6A modification.

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 MiR-128 suppresses metastatic capacity by targeting metadherin in breast cancer cells

2020 ◽  
Vol 53 (1) ◽  
Author(s):  
Danxia Cao ◽  
Han Zhu ◽  
Qian Zhao ◽  
Jianming Huang ◽  
Cixiang Zhou ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Cancer Metastasis ◽  
Histological Grade ◽  
Ectopic Expression ◽  
Cancer Cell Line ◽  
Breast Cancer Metastasis ◽  
Expression Level ◽  
Migration And Invasion ◽  
Clinical Samples

Abstract Background Breast cancer, the most common cancer in women worldwide, causes the vast majority of cancer-related deaths. Undoubtedly, tumor metastasis and recurrence are responsible for more than 90 percent of these deaths. MicroRNAs are endogenous noncoding RNAs that have been integrated into almost all the physiological and pathological processes, including metastasis. In the present study, the role of miR-128 in breast cancer was investigated. Results Compared to the corresponding adjacent normal tissue, the expression of miR-128 was significantly suppressed in human breast cancer specimens. More importantly, its expression level was reversely correlated to histological grade of the cancer. Ectopic expression of miR-128 in the aggressive breast cancer cell line MDA-MB-231 could inhibit cell motility and invasive capacity remarkably. Afterwards, Metadherin (MTDH), also known as AEG-1 (Astrocyte Elevated Gene 1) and Lyric that implicated in various aspects of cancer progression and metastasis, was further identified as a direct target gene of miR-128 and its expression level was up-regulated in clinical samples as expected. Moreover, knockdown of MTDH in MDA-MB-231 cells obviously impaired the migration and invasion capabilities, whereas re-expression of MTDH abrogated the suppressive effect caused by miR-128. Conclusions Overall, these findings demonstrate that miR-128 could serve as a novel biomarker for breast cancer metastasis and a potent target for treatment in the future.

scholarly journals Inhibition of Mmp-9 Expression through Nf-Kβ by Natural Compounds as a Possible Therapeutic Adjuvant Strategy in Breast Cancer: A Systematic Review

2019 ◽  
pp. 1-9
Author(s):  
Victor Alves de Oliveira ◽  
Diego Cipriano Chagas ◽  
Jefferson Rodrigues Amorim ◽  
Thaís Rodrigues Nogueira ◽  
Thais Alves Nogueira ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Cancer Metastasis ◽  
Natural Compounds ◽  
Breast Cancer Metastasis ◽  
Migration And Invasion ◽  
Transcriptional Level ◽  
Activator Protein 1 ◽  
Mitogen Activated Protein

MMP-9 expression may be induced at the transcriptional level in response to different agents. Due to its fundamental role in cancer progression, the control of MMP expression, especially MMP-9, is the possible target of future adjuvant therapies that seek to reduce metastases and angiogenesis in women with breast cancer. Therefore, the aim of this study was to search in the literature available evidences of extracts/or natural compounds that have potential therapeutic capacity to inhibit MMP-9 expression. Extracts and/or natural compounds identified in this review play a significant role in the inhibition of MMP-9 expression via NF-kβ, and may act on the prevention of metastases from primary breast tumors. The majority of the studies found have shown that natural products are capable of suppressing migration and invasion of breast cancer cells, thus inhibiting the formation of in vitro metastases. Further studies are warranted to understand the potential mechanisms of breast cancer metastasis from signaling cascades intrinsic to the tumor. Moreover, the NF-kβ, followed by Mitogen Activated Protein Kinases / Activator protein 1 (MAPK / AP-1) were the major pathways affected by the extracts and / or compounds studied. These pathways are directly linked to MMP-9 expression.

scholarly journals ERβ-mediated induction of cystatins results in suppression of TGFβ signaling and inhibition of triple-negative breast cancer metastasis

2018 ◽  
Vol 115 (41) ◽  
pp. E9580-E9589 ◽  
Author(s):  
Jordan M. Reese ◽  
Elizabeth S. Bruinsma ◽  
Adam W. Nelson ◽  
Igor Chernukhin ◽  
Jason S. Carroll ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Triple Negative Breast Cancer ◽  
Targeted Therapies ◽  
Cancer Metastasis ◽  
Triple Negative ◽  
Breast Cancer Metastasis ◽  
Tgfβ Signaling

Triple-negative breast cancer (TNBC) accounts for a disproportionately high number of deaths due to a lack of targeted therapies and an increased likelihood of distant recurrence. Estrogen receptor beta (ERβ), a well-characterized tumor suppressor, is expressed in 30% of TNBCs, and its expression is associated with improved patient outcomes. We demonstrate that therapeutic activation of ERβ elicits potent anticancer effects in TNBC through the induction of a family of secreted proteins known as the cystatins, which function to inhibit canonical TGFβ signaling and suppress metastatic phenotypes both in vitro and in vivo. These data reveal the involvement of cystatins in suppressing breast cancer progression and highlight the value of ERβ-targeted therapies for the treatment of TNBC patients.

scholarly journals Vitamin C Inhibits Triple-Negative Breast Cancer Metastasis by Affecting the Expression of YAP1 and Synaptopodin 2

Nutrients ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 2997 ◽  
Author(s):  
Liping Gan ◽  
Vladimir Camarena ◽  
Sushmita Mustafi ◽  
Gaofeng Wang
Keyword(s):  
Breast Cancer ◽  
Vitamin C ◽  
Triple Negative Breast Cancer ◽  
Cancer Metastasis ◽  
Triple Negative ◽  
Breast Cancer Metastasis ◽  
Migration And Invasion ◽  
Synaptopodin 2

Vitamin C supplementation has been shown to decrease triple-negative breast cancer (TNBC) metastasis. However, the molecular mechanism whereby vitamin C inhibits metastasis remains elusive. It has been postulated that vitamin C reduces the levels of HIF-1α, the master regulator of metastasis, by promoting its hydroxylation and degradation. Here, we show that vitamin C at 100 µM, a concentration achievable in the plasma in vivo by oral administration, blocks TNBC cell migration and invasion in vitro. The protein level of HIF-1α remains largely unchanged in cultured TNBC cells and xenografts, partially due to its upregulated transcription by vitamin C, suggesting that HIF-1α unlikely mediates the action of vitamin C on metastasis. Vitamin C treatment upregulates the expression of synaptopodin 2 and downregulates the expression of the transcription coactivator YAP1, both genes in the Hippo pathway. The changes in SYNPO2 and YAP1 expression were subsequently validated at mRNA and protein levels in cultured TNBC cells and xenografts. Further experiments showed that vitamin C treatment inhibits F-actin assembly and lamellipodia formation, which correlates with the changes in SYNPO2 and YAP1 expression. Overall, these results suggest that vitamin C inhibits TNBC metastasis by affecting the expression of SYNPO2 and YAP1. Vitamin C may thus have a potential role in the prevention and treatment of TNBC metastasis.

Sign in / Sign up

Export Citation Format

Share Document