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

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.

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

Journal of Cell Science ◽

10.1242/jcs.254888 ◽

2021 ◽

Vol 134 (8) ◽

Cited By ~ 1

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.

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

European Journal of Medicinal Plants ◽

10.9734/ejmp/2019/v29i230153 ◽

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.

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miRNA-dependent regulation of STIM1 expression in breast cancer

Scientific Reports ◽

10.1038/s41598-019-49629-5 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 1

Author(s):

Rashmi P. Kulkarni ◽

Asha Elmi ◽

Ethel Alcantara-Adap ◽

Satanay Hubrack ◽

Nancy Nader ◽

...

Keyword(s):

Breast Cancer ◽

Cell Line ◽

Cancer Progression ◽

Cancer Metastasis ◽

Cancer Cell Line ◽

Cell Types ◽

Breast Cancer Metastasis ◽

Protein Levels ◽

Mirna Species ◽

Different Cell Types

Abstract Store-operated Ca2+ entry (SOCE) has been shown to be important for breast cancer metastasis in xenograft mouse models. The ER Ca2+ sensor STIM1 and Orai plasma membrane Ca2+ channels molecularly mediate SOCE. Here we investigate the role of the microRNA machinery in regulating STIM1 expression. We show that STIM1 expression is regulated post-transcriptionally by the miRNA machinery and identify miR-223 and miR-150 as regulators of STIM1 expression in the luminal non-aggressive MCF7 breast cancer cell line. In contrast, STIM1 expression in the more aggressive basal triple-negative MDA-MB-231 cell line is not significantly modulated by a single miRNA species but is rather upregulated due to inhibition of the miRNA machinery through downregulation of Ago2. Consistently, overexpression of Ago2 results in decreased STIM1 protein levels in MDA-MB-231 cells. Clinically, STIM1 and Ago2 expression levels do not correlate with breast cancer progression, however in the basal subtype high STIM1 expression is associated with poorer survival. Our findings show that STIM1 expression is differentially regulated by the miRNA machinery in different cell types and argue for a role for this regulation in breast cancer.

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Cooperation of Cancer Stem Cell Properties and Epithelial-Mesenchymal Transition in the Establishment of Breast Cancer Metastasis

Journal of Oncology ◽

10.1155/2011/591427 ◽

2011 ◽

Vol 2011 ◽

pp. 1-7 ◽

Cited By ~ 30

Author(s):

Tetsu Hayashida ◽

Hiromitsu Jinno ◽

Yuko Kitagawa ◽

Masaki Kitajima

Keyword(s):

Breast Cancer ◽

Stem Cell ◽

Cancer Stem Cell ◽

Cancer Progression ◽

Cancer Metastasis ◽

Epithelial Mesenchymal Transition ◽

Metastatic Tumor ◽

Breast Cancer Metastasis ◽

Cell Junctions ◽

Mesenchymal Transition

Epithelial-mesenchymal transition (EMT) is a multistep process in which cells acquire molecular alterations such as loss of cell-cell junctions and restructuring of the cytoskeleton. There is an increasing understanding that this process may promote breast cancer progression through promotion of invasive and metastatic tumor growth. Recent observations imply that there may be a cross-talk between EMT and cancer stem cell properties, leading to enhanced tumorigenicity and the capacity to generate heterogeneous tumor cell populations. Here, we review the experimental and clinical evidence for the involvement of EMT in cancer stem cell theory, focusing on the common characteristics of this phenomenon.

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

The International Journal of Biological Markers ◽

10.5301/jbm.5000080 ◽

2014 ◽

Vol 29 (3) ◽

pp. 239-245 ◽

Cited By ~ 22

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.

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MicroRNA-18a promotes cancer progression through SMG1 suppression and mTOR pathway activation in nasopharyngeal carcinoma

Cell Death and Disease ◽

10.1038/s41419-019-2060-9 ◽

2019 ◽

Vol 10 (11) ◽

Cited By ~ 8

Author(s):

ShiJuan Mai ◽

RuoWen Xiao ◽

Lu Shi ◽

XiaoMin Zhou ◽

Te Yang ◽

...

Keyword(s):

Nasopharyngeal Carcinoma ◽

Cancer Progression ◽

Ectopic Expression ◽

Mtor Pathway ◽

Migration And Invasion ◽

Clinical Samples ◽

Antitumor Effects ◽

Barr Virus ◽

Epstein Barr

Abstract miR-18a has been reported to be upregulated in nasopharyngeal carcinoma (NPC) tissues by microarray assays. However, the roles and the underlying mechanisms of miR-18a in NPC remain poorly understood. Here we demonstrated by real-time RT-PCR that miR-18a expression is upregulated in NPC tissues, and positively correlated with tumor size and TNM stage. Moreover, miR-18a expression could be upregulated by NF-κB activation or Epstein-Barr virus encoded latent membrane protein 1 expression. The ectopic expression of miR-18a promoted NPC cell proliferation, migration and invasion, while the repression of miR-18a had opposite effects. Candidate genes under regulation by miR-18a were screened out through a whole-genome microarray assay, further identified by a reporter assay and verified in clinical samples. SMG1, a member of the phosphoinositide 3-kinase-related kinases family and an mTOR antagonist, was identified as functional target of miR-18a. Our results confirmed that miR-18a exerts its oncogenic role through suppression of SMG1 and activation of mTOR pathway in NPC cells. Importantly, in vivo xenograft tumor growth in nude mice was effectively inhibited by intratumor injection of miR-18a antagomir. Our data support an oncogenic role of miR-18a through a novel miR-18a/SMG1/mTOR axis and suggest that the antitumor effects of antagomir-18a may make it suitable for NPC therapy.

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Thidiazuron suppresses breast cancer progression via targeting miR-132 and miR-202-5p/PTEN axis mediated dysregulation of PI3K/AKT signaling pathway

Biochemistry and Cell Biology ◽

10.1139/bcb-2020-0377 ◽

2020 ◽

Author(s):

Hairul-Islam Ibrahim ◽

Mohammad Bani Ismail ◽

Rebai Ben Ammar ◽

Emad Ahmed

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Signaling Pathway ◽

Cancer Progression ◽

Cancer Metastasis ◽

Metastatic Cancer ◽

Akt Signaling ◽

Breast Cancer Metastasis ◽

Akt Signaling Pathway ◽

Stressful Environment

Chemo-resistance and metastatic disease development are the most common causes of breast cancer recurrence and death. Thidiazuron (TDZ) is a plant growth regulator, its biological role on human and animals has not been yet clarified. In the present study, we investigated the anticancer activity of this plant phytohormone on the drug resistant-triple negative breast cancer MDA-MB-231 cell line. Treatment of the breast cancer cells with TDZ (1-50 μM) caused more stressful environment and induced a significant increase in percentages of active caspases positive cells. In addition, TDZ treatment (5 and 10 μM) significantly attenuated the migration and the invasion activities of these highly metastatic cancer cells. Mechanistically, TDZ reducesd cancer progression and invasive activity through targeting miR-202-5p, which stimulatesd the expression of the phosphatase and tensin homolog (PTEN), the tumor suppressor that downregulates PI3K/AKT signaling pathway. In the meantime, TDZ treatment statistically upregulatesd the suppressor of breast cancer proliferation, miRNA-132 that is also implicated in dysregulating the TEN-AKT/the nuclear factor NFκB signaling pathway. Interestingly, our molecular docking analysis revealed potential non-covalent interaction between TDZ with AKT, PTEN and PI3K. These findings suggest that TDZ may suppresses breast cancer metastasis through targeting miRNA-132, miR-202-5p/PTEN and PI3K/AKT downstream molecules.

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Bromodomain-Containing Protein 4: A Dynamic Regulator of Breast Cancer Metastasis through Modulation of the Extracellular Matrix

International Journal of Breast Cancer ◽

10.1155/2012/670632 ◽

2012 ◽

Vol 2012 ◽

pp. 1-7 ◽

Cited By ~ 15

Author(s):

Jude Alsarraj ◽

Kent W. Hunter

Keyword(s):

Breast Cancer ◽

Cancer Progression ◽

Cancer Metastasis ◽

Susceptibility Gene ◽

Breast Cancer Metastasis ◽

Primary Tumors ◽

Inherited Susceptibility ◽

Complex Process ◽

Host Genetic

Metastasis is an extremely complex process that accounts for most cancer-related deaths. Malignant primary tumors can be removed surgically, but the cells that migrate, invade, and proliferate at distant organs are often the cells that prove most difficult to target therapeutically. There is growing evidence that host factors outside of the primary tumors are of major importance in the development of metastasis. Recently, we have shown that the bromodomain-containing protein 4 or bromodomain 4 (Brd4) functions as an inherited susceptibility gene for breast cancer progression and metastasis. In this paper, we will discuss that host genetic background on which a tumor arises can significantly alter the biology of the subsequent metastatic disease, and we will focus on the role ofBrd4in regulating metastasis susceptibility.

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

Oncogene ◽

10.1038/s41388-020-01562-y ◽

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.

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