scholarly journals Small Molecules Inhibit Extranuclear Signaling by Estrogen: A Promising Strategy to Halt Breast Cancer Progression and Metastasis

2020 ◽  
Author(s):  
Imaobong Etti ◽  
Chukwuemeka Nwafor ◽  
Grace Essien
Keyword(s):  
Breast Cancer ◽  
Small Molecules ◽  
Cancer Progression ◽  
Cancer Metastasis ◽  
Pharmacokinetic Profile ◽  
Breast Cancer Metastasis ◽  
Sex Hormone ◽  
Binding Interaction ◽  
Vicinal Diol ◽  
Extranuclear Signaling

The sex hormone estrogen plays critical roles in reproductive and sexual development. It regulates the expression and activity of key signaling molecules critical in various cellular signaling pathways. These signals are mediated by its binding to estrogen receptors alpha (ERα) and beta (ERβ). ERα has been shown to greatly participate in extranuclear signaling, inducing tumorogenesis and breast cancer metastasis. Small molecules from plants are reported with better selectivity toward tumorigenic cells with negligible toxicity when compared to their synthetic counterpart. The molecules used in this study were first probed for their drug-likeness and their pharmacokinetic profile was elucidated before docking them to the ligand binding domain of the human ERα followed by a post docking prime analysis. All tested molecules had good drug-like and pharmacokinetic properties when compared to about 95% of orally available drugs as predicted by qikprop. The docking results revealed a strong binding interaction with ERα, influenced mostly by the vicinal diol groups of the studied molecules. These resulted in a conformational change, inducing receptor dimerization and altering the interactions of the sex hormone with other proteins. The studied ligands are promising in strongly inhibiting the binding of estrogen to ERα, thus limiting its extranuclear signaling.

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 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.

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.

Anti-PITPNM3 small molecular compounds reverse breast cancer metastasis by targeting PITPNM3.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e15005-e15005
Author(s):  
Chang Gong ◽  
Zihao Liu ◽  
Qun Lin ◽  
Yu Shi ◽  
Qing Luo ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Small Molecules ◽  
Cancer Metastasis ◽  
Breast Cancer Metastasis ◽  
Migration And Invasion ◽  
Invasion Assay ◽  
Potential Binding ◽  
Binding Pockets ◽  
Small Molecular Inhibitors ◽  
High Diversity

e15005 Background: Recent studies highlight the fundamental roles of PITPNM3 in breast cancer metastasis. PITPNM3 is identified as the functional receptor of CCL18 and promotes breast cancer cell invasion and metastasis by binding with CCL18. Since anti-CCL18 neutralized antibodies shows medium binding affinity which restricts their clinical application, small molecular inhibitors targeting PITPNM3 are needed to be further investigated. Therefore, we identified several first in class small molecular inhibitors potentially targeting PITPNM3 and can inhibit breast cancer metastasis conducted by PITPNM3 activation. Methods: We performed computer-assisted drug design by constructing PITPNM3 homology model, characterizing potential binding pockets and docking preselected high diversity structured small molecule compounds into the static PITPNM3 model. Top 100 small molecules in silico scores were selected and screened through basic experiments. After screening, the anti-metastasis effects of selected compounds were tested through transwell migration and invasion assay. Immunofluorescence and qPCR were applied to confirm the expression of vimentin and CDH1. Western blot were used to clarify the inhibition effects of selected compounds on PITPNM3 signaling pathways. Results: By using homology remodeling, we successfully constructed the PITPNM3(680-920aa) protein model. The PITPNM3(680-920aa) domain is responsible for interacting with PYK2 and phosphorylating PYK2. The phosphorylation of PYK2 conducted by PITPNM3 signaling pathway will lead to metastasis and epithelial-mesenchymal transition (EMT) of breast cancer cells. We then characterized the potential binding pockets of this static model and a druggable site was founded. More than 50K molecules with high diversity were docked into this druggable site and scored through their docking performance. Finally, top 100 scored small molecules were selected. In addition, through 1 rounds of toxicity screening, 1 round of transwell migration assay screening and 1 round of transwell invasion assay screening, 4 small molecules with higher bioactivity is identified and 1 compound with the highest bioactivity as well as docking performance among 50K small molecules is chose. This compound can inhibit CCL18 treatment as well as tumor associated macrophage co-culture mediated migration and invasion. Besides, it can also inhibit the phophorylation of PYK2 and Src without inhibition the expression of PITPNM3. Conclusions: Our findings identify the first-in-class anti-PITPNM3 small molecule inhibitors. These compounds can inhibit PITPNM3 signaling pathway and reverse 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 Chemotherapy-exacerbated Breast Cancer Metastasis: A Paradox Explainable by Stress Response

2018 ◽  
Author(s):  
Justin D. Middleton ◽  
Daniel G. Stover ◽  
Tsonwin Hai
Keyword(s):  
Breast Cancer ◽  
Stress Response ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Cancer Biology ◽  
Cancer Metastasis ◽  
Blood Stream ◽  
Breast Cancer Metastasis ◽  
Host Cells ◽  
Primary Tumors

An emerging picture in cancer biology is that, paradoxically, chemotherapy can actively induce changes that favor cancer progression. These pro-cancer changes can be either inside (intrinsic) or outside (extrinsic) the cancer cells. In this review, we will discuss the extrinsic pro-cancer effect of chemotherapy; that is, the effect of chemotherapy on the non-cancer host cells to promote cancer progression. We will focus on metastasis, and will first discuss recent data from mouse models of breast cancer. Intriguingly, despite reducing the size of primary tumors, chemotherapy changes the tumor microenvironment, resulting in an increased escape of cancer cells into the blood stream. Furthermore, chemotherapry changes the tissue microenvironment at the distant sites, making it more hospitable to cancer cells upon their arrival. We will then discuss the idea and evidence that these devastating pro-metastatic effects of chemotherapy can be explained in the context of stress response. At the end, we will discuss the potential relevance of these mouse data to human breast cancer and their implication on chemotherapy in the clinic.

scholarly journals Differential MicroRNA Landscape Triggered by Estrogens in Cancer Associated Fibroblasts (CAFs) of Primary and Metastatic Breast Tumors

Cancers ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 412 ◽  
Author(s):  
Adele Vivacqua ◽  
Maria Muoio ◽  
Anna Miglietta ◽  
Marcello Maggiolini
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Cancer Metastasis ◽  
Metastatic Breast ◽  
Breast Tumors ◽  
Breast Cancer Metastasis ◽  
Cutaneous Metastasis ◽  
Breast Cancer Progression ◽  
Main Role ◽  
Cancer Associated Fibroblasts

Cancer associated fibroblasts (CAFs) play a main role in breast cancer progression and metastasis. Estrogens modulate in breast CAFs the expression of microRNAs (miRNAs) that are involved in the development of many tumors. In order to provide novel insights on the regulation of miRNAs by estrogens in breast cancer, we analyzed the expression of 754 miRNAs in CAFs obtained from primary mammary tumors and CAFs derived from a cutaneous breast cancer metastasis. Using the TaqMan™ Human MicroRNA Array, we found that 17β-estradiol (E2) modulates numerous peculiar and common miRNAs in CAFs derived from primary and the metastatic malignancies. In particular, we assessed that E2 modulates 133 miRNAs (41 up and 92 downregulated) in CAFs derived from primary breast tumors, whereas E2 modulates 415 miRNAs (399 up and 16 downregulated) in CAFs derived from a cutaneous metastasis of breast carcinoma. Therefore, a number of miRNAs three times higher in metastatic CAFs with respect to primary breast CAFs was found modulated by E2. Our findings shed new light on the cumulative regulation of miRNAs by E2 in the main players of the tumor microenvironment as CAFs. Moreover, our data may be taken into consideration that is useful toward innovative prognostic and therapeutic approaches in breast cancer progression.

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