scholarly journals JUNB suppresses distant metastasis by influencing the initial metastatic stage

2021 ◽  
Author(s):  
Juliane Wutschka ◽  
Bettina Kast ◽  
Melanie Sator-Schmitt ◽  
Sila Appak-Baskoy ◽  
Jochen Hess ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Microenvironment ◽  
Cancer Progression ◽  
Distant Metastasis ◽  
Cancer Metastasis ◽  
Human Cancer ◽  
Tumor Resection ◽  
Clinical Situation ◽  
Breast Cancer Metastasis ◽  
Dependent Manner

AbstractThe complex interactions between cells of the tumor microenvironment and cancer cells are considered a major determinant of cancer progression and metastasis. Yet, our understanding of the mechanisms of metastatic disease is not sufficient to successfully treat patients with advanced-stage cancer. JUNB is a member of the AP-1 transcription factor family shown to be frequently deregulated in human cancer and associated with invasion and metastasis. A strikingly high stromal JUNB expression in human breast cancer samples prompted us to functionally investigate the consequences of JUNB loss in cells of the tumor microenvironment on cancer progression and metastasis in mice. To adequately mimic the clinical situation, we applied a syngeneic spontaneous breast cancer metastasis model followed by primary tumor resection and identified stromal JUNB as a potent suppressor of distant metastasis. Comprehensive characterization of the JUNB-deficient tumor microenvironment revealed a strong influx of myeloid cells into primary breast tumors and lungs at early metastatic stage. In these infiltrating neutrophils, BV8 and MMP9, proteins promoting angiogenesis and tissue remodeling, were specifically upregulated in a JUNB-dependent manner. Taken together, we established stromal JUNB as a strong suppressor of distant metastasis. Consequently, therapeutic strategies targeting AP-1 should be carefully designed not to interfere with stromal JUNB expression as this may be detrimental for cancer patients.

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

2011 ◽  
Vol 2011 ◽  
pp. 1-7 ◽  
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.

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.

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

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.

scholarly journals Exosomal MicroRNAs and Organotropism in Breast Cancer Metastasis

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1827 ◽  
Author(s):  
Grace L. Wong ◽  
Sara Abu Jalboush ◽  
Hui-Wen Lo
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Tumor Microenvironment ◽  
Cancer Metastasis ◽  
Current Knowledge ◽  
Metastatic Breast ◽  
Tumor Stroma ◽  
Breast Cancer Metastasis ◽  
Exosomal Mirnas ◽  
Made In

Breast cancer is the most frequent malignancy for women in which one in eight women will be diagnosed with the disease in their lifetime. Despite advances made in treating primary breast cancer, there is still no effective treatment for metastatic breast cancer. Consequently, metastatic breast cancer is responsible for 90% of breast cancer-related deaths while only accounting for approximately one third of all breast cancer cases. To help develop effective treatments for metastatic breast cancer, it is important to gain a deeper understanding of the mechanisms by which breast cancer metastasizes, particularly, those underlying organotropism towards brain, bone, and lungs. In this review, we will primarily focus on the roles that circulating exosomal microRNAs (miRNAs) play in organotropism of breast cancer metastasis. Exosomes are extracellular vesicles that play critical roles in intercellular communication. MicroRNAs can be encapsulated in exosomes; cargo-loaded exosomes can be secreted by tumor cells into the tumor microenvironment to facilitate tumor–stroma interactions or released to circulation to prime distant organs for subsequent metastasis. Here, we will summarize our current knowledge on the biogenesis of exosomes and miRNAs, mechanisms of cargo sorting into exosomes, the exosomal miRNAs implicated in breast cancer metastasis, and therapeutic exosomal miRNAs.

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

2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
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.

Breast Cancer Metastasis: Role of Tumor Microenvironment and Resident Macropahges

2016 ◽  
Vol 1 (1) ◽  
pp. 48
Author(s):  
Khemraj Singh Baghel ◽  
Smrati Bhadauria
Keyword(s):  
Breast Cancer ◽  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Metastatic Breast ◽  
Breast Cancer Metastasis ◽  
The Body ◽  
Tissue Remodelling ◽  
Mesenchymal Transition

Metastatic breast cancer is a stage of breast cancer wherever the disease has spread to distant parts of the body. Onset of metastasis is one of the biggest obstacles to the successful treatment of cancer. The potential of a tumor cell to metastasize profoundly depends on its microenvironment, or “niche” interactions with local components. Macrophages provide tropic support to tumors. Resident macrophages contribute a set of common functions, including their capability to defend against microbial infections, to maintain normal cell turnover and tissue remodelling, and to help repair sites of injury. Macrophages are recruited into the tumor microenvironment where they differentiate to become Tumor-associated-macrophages (TAMs). TAMs are the most abundant subpopulation of tumor-stroma and actively drive cancer cell invasion and metastasis. Cancer metastasis is not solely regulated by the deregulation of metastasis promoting or suppressing genes in cancer cells. Recently the interaction between the stromal cells and cancer cells has been demonstrated to promote cancer metastasis. TAMs can advocate epithelial-mesenchymal transition of cancer cells. Loss of e-cadherin, a major phenomenon of epithelial to mesenchymal transition (EMT), reduces adhesiveness and releases cancer cells to distant (secondary) sites. A positive correlation between tumor progression and the expression of matrix metallo proteinases (MMPs) in tumor tissues has been demonstrated in numerous human and animal studies. The dynamic interactions of cancer-cells with TAMs actively promote invasion-metastasis cascade through intercellular-signalling-networks that need better elucidation.

scholarly journals Heparan Sulfate and Heparanase as Modulators of Breast Cancer Progression

2013 ◽  
Vol 2013 ◽  
pp. 1-11 ◽  
Author(s):  
Angélica M. Gomes ◽  
Mariana P. Stelling ◽  
Mauro S. G. Pavão
Keyword(s):  
Breast Cancer ◽  
Heparan Sulfate ◽  
Tumor Progression ◽  
Cancer Progression ◽  
Cancer Metastasis ◽  
Antitumor Agents ◽  
Breast Cancer Metastasis ◽  
Tumor Type ◽  
Matrix Assembly ◽  
Genetic Components

Breast cancer is defined as a cancer originating in tissues of the breast, frequently in ducts and lobules. During the last 30 years, studies to understand the biology and to treat breast tumor improved patients’ survival rates. These studies have focused on genetic components involved in tumor progression and on tumor microenvironment. Heparan sulfate proteoglycans (HSPGs) are involved in cell signaling, adhesion, extracellular matrix assembly, and growth factors storage. As a central molecule, HSPG regulates cell behavior and tumor progression. HS accompanied by its glycosaminoglycan counterparts regulates tissue homeostasis and cancer development. These molecules present opposite effects according to tumor type or cancer model. Studies in this area may contribute to unveil glycosaminoglycan activities on cell dynamics during breast cancer exploring these polysaccharides as antitumor agents. Heparanase is a potent tumor modulator due to its protumorigenic, proangiogenic, and prometastatic activities. Several lines of evidence indicate that heparanase is upregulated in all human sarcomas and carcinomas. Heparanase seems to be related to several aspects regulating the potential of breast cancer metastasis. Due to its multiple roles, heparanase is seen as a target in cancer treatment. We will describe recent findings on the function of HSPGs and heparanase in breast cancer behavior and progression.

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.

Sign in / Sign up

Export Citation Format

Share Document