scholarly journals Sodium Channel Nav1.5 Controls Epithelial-to-Mesenchymal Transition and Invasiveness in Breast Cancer Cells Through its Regulation by the Salt-Inducible Kinase-1

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Frédéric Gradek ◽  
Osbaldo Lopez-Charcas ◽  
Stéphanie Chadet ◽  
Lucile Poisson ◽  
Lobna Ouldamer ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Transcription Factor ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Epithelial To Mesenchymal Transition ◽  
Aberrant Expression ◽  
Mesenchymal Transition ◽  
Voltage Gated Sodium Channels ◽  
Cell Invasiveness ◽  
Mcf 7

AbstractLoss of epithelial polarity and gain in invasiveness by carcinoma cells are critical events in the aggressive progression of cancers and depend on phenotypic transition programs such as the epithelial-to-mesenchymal transition (EMT). Many studies have reported the aberrant expression of voltage-gated sodium channels (NaV) in carcinomas and specifically the NaV1.5 isoform, encoded by the SCN5A gene, in breast cancer. NaV1.5 activity, through an entry of sodium ions, in breast cancer cells is associated with increased invasiveness, but its participation to the EMT has to be clarified. In this study, we show that reducing the expression of NaV1.5 in highly aggressive human MDA-MB-231 breast cancer cells reverted the mesenchymal phenotype, reduced cancer cell invasiveness and the expression of the EMT-promoting transcription factor SNAI1. The heterologous expression of NaV1.5 in weakly invasive MCF-7 breast cancer cells induced their expression of both SNAI1 and ZEB1 and increased their invasive capacities. In MCF-7 cells the stimulation with the EMT-activator signal TGF-β1 increased the expression of SCN5A. Moreover, the reduction of the salt-inducible kinase 1 (SIK1) expression promoted NaV1.5-dependent invasiveness and expression of EMT-associated transcription factor SNAI1. Altogether, these results indicated a prominent role of SIK1 in regulating NaV1.5-dependent EMT and invasiveness.

scholarly journals Interleukin-8 Promotes Epithelial-to-Mesenchymal Transition via Downregulation of Mir-200 Family in Breast Cancer Cells

2020 ◽  
Vol 19 ◽  
pp. 153303382097967
Author(s):  
Jin Zhang ◽  
Nan Shao ◽  
Xiaoyu Yang ◽  
Chuanbo Xie ◽  
Yawei Shi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Breast Cancer Cells ◽  
Epithelial To Mesenchymal Transition ◽  
Cancer Cell Line ◽  
Control Group ◽  
Mesenchymal Transition ◽  
Mcf 7

The microRNA-200 (miR-200) family has been reported to be vital for the inhibition of epithelial-to-mesenchymal transition (EMT) in tumor cells. The miR-200 family represents a complex multi-factorial regulatory network which has not been well described in breast cancer. This study aimed to clarify the underlying regulatory association between IL-8 and miR-200 family in the process of EMT in breast cancer cell. In estrogen-receptor (ER) positive breast cancer cell line MCF-7, IL-8 overexpression cells were performed by lentivirus transfection as endogenous regulation with additional exogenous IL-8 stimulation. Transient overexpressions of miR-200 family were performed after endogenous or exogenous IL-8 overexpression in MCF-7 cells. IL-8 knockdown cells were constructed via siRNA and shRNA transfection in triple negative breast cancer cell line MDA-MB-231. N-cadherin, vimentin and ZEB2 were down-regulated and E-cadherin was up-regulated in IL-8 knockdown group compared with control group. On the other hand, N-cadherin, vimentin and ZEB2 were up-regulated and E-cadherin was down-regulated in IL-8 overexpression group compared with control group. This indicated IL-8 promotes EMT in breast cancer cells. Transwell assay showed that IL-8 increased the migration and invasiveness of tumor cells. Furthermore, we performed transient overexpression of miR-200 family after endogenous or exogenous IL-8 overexpression in MCF-7 cells, which showed that the miR-200 family could inhibit EMT induced by IL-8. IL-8 promoted EMT via downregulation of miR-200 family expression in breast cancer cells and increases tumor cell migration and invasion.

scholarly journals Collagen Fiber Array of Peritumoral Stroma Influences Epithelial-to-Mesenchymal Transition and Invasive Potential of Mammary Cancer Cells

2019 ◽  
Vol 8 (2) ◽  
pp. 213 ◽  
Author(s):  
Marco Franchi ◽  
Valentina Masola ◽  
Gloria Bellin ◽  
Maurizio Onisto ◽  
Konstantinos-Athanasios Karamanos ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Basement Membrane ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Breast Cancer Cells ◽  
Collagen Fiber ◽  
Epithelial To Mesenchymal Transition ◽  
Mesenchymal Transition ◽  
Mcf 7

: Interactions of cancer cells with matrix macromolecules of the surrounding tumor stroma are critical to mediate invasion and metastasis. In this study, we reproduced the collagen mechanical barriers in vitro (i.e., basement membrane, lamina propria under basement membrane, and deeper bundled collagen fibers with different array). These were used in 3D cell cultures to define their effects on morphology and behavior of breast cancer cells with different metastatic potential (MCF-7 and MDA-MB-231) using scanning electron microscope (SEM). We demonstrated that breast cancer cells cultured in 2D and 3D cultures on different collagen substrates show different morphologies: i) a globular/spherical shape, ii) a flattened polygonal shape, and iii) elongated/fusiform and spindle-like shapes. The distribution of different cell shapes changed with the distinct collagen fiber/fibril physical array and size. Dense collagen fibers, parallel to the culture plane, do not allow the invasion of MCF-7 and MDA-MB-231 cells, which, however, show increases of microvilli and microvesicles, respectively. These novel data highlight the regulatory role of different fibrillar collagen arrays in modifying breast cancer cell shape, inducing epithelial-to-mesenchymal transition, changing matrix composition and modulating the production of extracellular vesicles. Further investigation utilizing this in vitro model will help to demonstrate the biological roles of matrix macromolecules in cancer cell invasion in vivo.

scholarly journals Silver Nanoparticles Modulate the Epithelial-to-Mesenchymal Transition in Estrogen-Dependent Breast Cancer Cells In Vitro

2021 ◽  
Vol 22 (17) ◽  
pp. 9203
Author(s):  
Michał Rakowski ◽  
Szymon Porębski ◽  
Agnieszka Grzelak
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Mitochondrial Membrane ◽  
Breast Cancer Cells ◽  
Epithelial To Mesenchymal Transition ◽  
Calcium Flux ◽  
Oxygen Species ◽  
Mesenchymal Transition ◽  
Marker Proteins ◽  
Mcf 7

Silver nanoparticles (AgNPs) are frequently detected in many convenience goods, such as cosmetics, that are applied directly to the skin. AgNPs accumulated in cells can modulate a wide range of molecular pathways, causing direct changes in cells. The aim of this study is to assess the capability of AgNPs to modulate the metastasis of breast cancer cells through the induction of epithelial-to-mesenchymal transition (EMT). The effect of the AgNPs on MCF-7 cells was investigated via the sulforhodamine B method, the wound healing test, generation of reactive oxygen species (ROS), the standard cytofluorimetric method of measuring the cell cycle, and the expression of EMT marker proteins and the MTA3 protein via Western blot. To fulfill the results, calcium flux and HDAC activity were measured. Additionally, mitochondrial membrane potential was measured to assess the direct impact of AgNPs on mitochondria. The results indicated that the MCF-7 cells are resistant to the cytotoxic effect of AgNPs and have higher mobility than the control cells. Treatment with AgNPs induced a generation of ROS; however, it did not affect the cell cycle but modulated the expression of EMT marker proteins and the MTA3 protein. Mitochondrial membrane potential and calcium flux were not altered; however, the AgNPs did modulate the total HDAC activity. The presented data support our hypothesis that AgNPs modulate the metastasis of MCF-7 cells through the EMT pathway. These results suggest that AgNPs, by inducing reactive oxygen species generation, alter the metabolism of breast cancer cells and trigger several pathways related to metastasis.

scholarly journals Induced Tamoxifen Resistance is Mediated by Increased Methylation of E-Cadherin in Estrogen Receptor-Expressing Breast Cancer Cells

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Qi Wang ◽  
Melisa Gun ◽  
Xing-yu Hong
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Epithelial To Mesenchymal Transition ◽  
Breast Cancers ◽  
Mesenchymal Transition ◽  
Tamoxifen Resistant ◽  
Mcf 7 ◽  
E Cadherin

Abstract Estrogen receptor-positive breast cancers are treated with tamoxifen, a drug that competitively inhibits the binding of estrogen to its receptor. Resistance to tamoxifen is a major hurdle in effective management of target breast cancer patient population. A number of dynamic changes within the tumor microenvironment, including the phenomenon of epithelial to mesenchymal transition (EMT), determine the response to endocrine therapy. EMT is marked by silencing or suppression of epithelial marker, E-Cadherin and we found significantly down-regulated E-Cadherin, among other epithelial markers, and a significantly up-regulated mesenchymal marker, Twist, among other mesenchymal markers, in a model system that comprised of tamoxifen sensitive MCF-7 cells and their tamoxifen-resistant counterparts, MCF-7-TAM, developed by chronic and escalating exposure of parental cells to tamoxifen. Further, E-cadherin, but not Twist, was differentially expressed in MCF-7-TAM cells because of differential methylation. Treatment with demethylating agent 5-azacytidine increased the expression of E-cadherin thus verifying a role of methylation in its silencing and, moreover, 5-azacytidine treatment also re-sensitized MCF-7-TAM cells to tamoxifen, as evaluated by assays for viability, apoptosis and migration potential. The 5-azacytidine effects were similar to effects of E-cadherin overexpression in MCF-7-TAM cells. This work describes novel mechanism of E-cadherin downregulation in tamoxifen resistant breast cancer cells. Further studies are needed to exploit this information for betterment of breast cancer therapy.

scholarly journals The Transcription Factor Snail Mediates Epithelial to Mesenchymal Transitions by Repression of Estrogen Receptor-α

2007 ◽  
Vol 21 (12) ◽  
pp. 2907-2918 ◽  
Author(s):  
Archana Dhasarathy ◽  
Masahiro Kajita ◽  
Paul A. Wade
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Transcription Factor ◽  
Cancer Cells ◽  
Dna Sequences ◽  
Breast Cancer Cells ◽  
Cancer Metastasis ◽  
Epithelial To Mesenchymal Transition ◽  
Phenotypic Properties ◽  
Mesenchymal Transition

Abstract The estrogen receptor (ER)-α (ESR1) is a key regulatory molecule in mammary epithelial cell development. Loss of ER-α in breast cancer is correlated with poor prognosis, increased recurrence after treatment, and an elevated incidence of metastasis. A proposed molecular pathway by which ER-α acts to constrain invasive growth in breast cancer cells involves direct, ER-α-dependent expression of metastasis-associated protein 3, a cell-type-specific component of the Mi-2/NuRD chromatin remodeling complex. MTA3 in turn represses expression of Snail, a transcription factor linked to epithelial to mesenchymal transition and cancer metastasis. To elucidate its role(s) in epithelial to mesenchymal transition (EMT), we expressed Snail in the noninvasive, ER-α-positive MCF-7 cell line. Snail expression led to decreased cell-cell adhesion and increased cell invasiveness. Furthermore, we observed loss of ER-α expression at both the RNA and protein level that was accompanied by direct interaction of Snail with regulatory DNA sequences at the ESR1 locus. A consequence of loss of ER-α function in this system was the increased abundance of key components of the TGF-β signaling pathway. Thus, cross-talk among ER-α, Snail, and the TGF-β pathway appears to control critical phenotypic properties of breast cancer cells.

scholarly journals Anti-Proliferation, Pro-Apoptosis and Anti-Migration Effects of Ginkgolic Acid C13:0 Isolated from Ginkgo Biloba Exocarp in MCF-7 and 4T-1 Breast Cancer Cells

2018 ◽  
Author(s):  
Da-Yu Zhou ◽  
Chun-Ying Jiang ◽  
Cheng-Hao Fu ◽  
Ping Chang ◽  
Jia-Di Wu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Anticancer Agents ◽  
Ginkgo Biloba ◽  
Breast Cancer Cells ◽  
Epithelial To Mesenchymal Transition ◽  
Vimentin Expression ◽  
Apoptosis Pathway ◽  
Mesenchymal Transition ◽  
Mcf 7

Ginkgolic acids (GA) have been reported to exhibit anticancer properties, however, the mechanisms remain unclear. This study aims to investigate the mechanisms of GA C13:0 that was isolated from Ginkgo biloba exocarp (GBE) for anti-proliferation, pro-apoptosis and anti-migration effects in human MCF-7 and mouse 4T-1 breast cancer cells. The cytotoxic effect, apoptosis induction and migration inhibition were measured using MTT, TUNEL and Wound healing assays. The expression of mRNA and protein were determined using qPCR and Western blot. Our results showed that no cytotoxicity was found at concentrations of C13:0 below 100µM. The effects of GA C13:0 was further demonstrated by up-regulation of the Bax/Bcl-2 apoptosis pathway and the expression of Apaf-1 protein in the mitochondria. In addition, GA C13:0 also suppressed cell migration and epithelial to mesenchymal transition (EMT) with the increase of E-cadherin expression accompanied by the decrease of Snail, MMP-2, MMP-9 and Vimentin expression. Moreover, GA C13:0 induced cytochrome P450 (CYP) 1B1 expression in aryl hydrocarbon receptor (AhR) pathway. Notably, the up-regulation of CYP1B1 also might play a pivotal regulatory role in mitochondrial and EMT pathways in MCF-7 and 4T-1 cells. Our results may have implications for the development of anticancer agents containing GA as functional additives.

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