scholarly journals Parthenolide Inhibits Migration and Reverses the EMT Process in Breast Cancer Cells by Suppressing TGFβ and TWIST1

2021 ◽  
Author(s):  
Hazera Binte Sufian ◽  
Julianna Maria Santos ◽  
Zeina Shreen Khan ◽  
Maliha Tabassum Munir ◽  
MD Khurshidul Zahid ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Cell Viability ◽  
Cell Lines ◽  
Transforming Growth Factor Beta ◽  
Cancer Metastasis ◽  
Transforming Growth Factor ◽  
Breast Cancer Metastasis ◽  
Control Treatment ◽  
Mesenchymal Transition

Abstract Breast cancer metastasis is the leading cause of mortality among breast cancer patients. Epithelial to mesenchymal transition (EMT) is a biological process that plays a fundamental role in facilitating breast cancer metastasis. The present study assessed the efficacy of parthenolide (PTL,Tanacetum parthenium) on EMT and its underlying mechanisms in in both lowly metastatic, estrogen-receptor positive, MCF-7 cells and highly metastatic triple-negative MDA-MB-231 cells. Cell viability was determined by MTT (3-(4,5-dimethy lthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay. Apoptosis was analyzed by FITC (fluorescein isothiocyanate) annexin V apoptosis detection kit. The monolayer wound scratch assay was employed to evaluate cancer cell migration. Proteins were separated and identified by Western blotting. Gene expression was analyzed by quantitative real-time PCR. PTL treatment significantly reduced cell viability and migration while inducing apoptosis in both cell lines. Also, PTL treatment reverses the EMT process by decreasing the mesenchymal marker vimentin and increasing the epithelial marker E-cadherin compared to the control treatment. Importantly, PTL downregulates TWIST1 (a transcription factor and regulator of EMT) gene expression concomitant with the reduction of transforming growth factor beta (TGFβ) protein and gene expression in both cell lines. Our findings provide insights into the therapeutic potential of PTL to mitigate EMT and breast cancer metastasis. These promising results demand in vivo studies.

scholarly journals Loss of BRMS1 Promotes a Mesenchymal Phenotype through NF-κB-Dependent Regulation ofTwist1

2014 ◽  
Vol 35 (1) ◽  
pp. 303-317 ◽  
Author(s):  
Yuan Liu ◽  
Marty W. Mayo ◽  
Aizhen Xiao ◽  
Emily H. Hall ◽  
Elianna B. Amin ◽  
...  
Keyword(s):  
Transforming Growth Factor Beta ◽  
Cancer Metastasis ◽  
Epithelial To Mesenchymal Transition ◽  
Transforming Growth Factor ◽  
Breast Cancer Metastasis ◽  
Metastasis Suppressor ◽  
Mesenchymal Phenotype ◽  
Mesenchymal Transition ◽  
Metastasis Suppressor 1 ◽  
Promoter Occupancy

Breast cancer metastasis suppressor 1 (BRMS1) is downregulated in non-small cell lung cancer (NSCLC), and its reduction correlates with disease progression. Herein, we investigate the mechanisms through which loss of theBRMS1gene contributes to epithelial-to-mesenchymal transition (EMT). Using a short hairpin RNA (shRNA) system, we show that loss of BRMS1 promotes basal and transforming growth factor beta-induced EMT in NSCLC cells. NSCLC cells expressingBRMS1shRNAs (BRMS1knockdown [BRMS1KD]) display mesenchymal characteristics, including enhanced cell migration and differential regulation of the EMT markers. Mesenchymal phenotypes observed inBRMS1KDcells are dependent on RelA/p65, the transcriptionally active subunit of nuclear factor kappa B (NF-κB). In addition, chromatin immunoprecipitation analysis demonstrates that loss ofBRMS1increasesTwist1promoter occupancy of RelA/p65 K310—a key histone modification associated with increased transcription. Knockdown ofTwist1results in reversal ofBRMS1KD-mediated EMT phenotypic changes. Moreover, in our animal model,BRMS1KD/Twist1KDdouble knockdown cells were less efficient in establishing lung tumors thanBRMS1KDcells. Collectively, this study demonstrates that loss of BRMS1 promotes malignant phenotypes that are dependent on NF-κB-dependent regulation ofTwist1. These observations offer fresh insight into the mechanisms through which BRMS1 regulates the development of metastases in NSCLC.

Melatonin down-regulates microRNA-10a and decreases invasion and migration of triple-negative breast cancer cells

2019 ◽  
Vol 2 (2) ◽  
pp. 86-99
Author(s):  
Jessica Gisleine de Oliveira ◽  
Jéssica Helena de Mora Marques ◽  
Jéssica Zani Lacerda ◽  
Lívia Carvalho Ferreira ◽  
Marcelo Mafra Campos Coelho ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Cell Viability ◽  
Cancer Metastasis ◽  
Gene Expression Regulation ◽  
Mirna Sequence ◽  
Mesenchymal Transition ◽  
Invasion And Migration ◽  
And Migration ◽  
E Cadherin

Breast cancer metastasis is one of the main factors associated with high mortality rates among patients. MicroRNAs (miRNAs) play an important role in gene expression regulation, and are associated with the metastatic process in breast cancer. Melatonin, a hormone secreted mainly in the pineal gland, has several oncostatic effects. The aim of this study was to investigate the action of melatonin in the modulation of miRNA-10a-5p and its association with metastatic mechanisms. We have evaluated the effects of melatonin on cell viability in MDA-MB-468 cell line after 24 hours of treatment. MDA-MB-468 and MDA-MB-231 cells were either transfected with inhibitor of miR-10a, or received a scrambled miRNA sequence as a negative control, then these cells were treated with or without melatonin. Gene expression of miR-10a was verified by real-time PCR. Invasion and migration assay using matrigel inserts were performed. The protein expression was analyzed by western blotting to quantify the epithelial-mesenchymal transition (EMT) markers (E-cadherin, claudin 7, and vimentin) and proliferation marker (PIK3CA). Our results showed that melatonin (1 mM) significantly decreased cell viability, and also affected miR-10a expression, which suppressed cell invasion and migration. Melatonin reduced vimentin and claudin 7 protein expressions, and increased E-cadherin. In contrast, inhibition of miR-10a reduced vimentin and did not modulate claudin 7 and E-cadherin. In conclusion, we demonstrated the effectiveness of melatonin in decreasing miR-10a, affecting invasion and migration, and proteins involved with the EMT process, which supports its potential role in the regulation of metastasis.  

scholarly journals Palladium nanoplates scotch breast cancer lung metastasis by constraining epithelial-mesenchymal transition

2020 ◽  
Author(s):  
Shunhao Wang ◽  
Jingchao Li ◽  
Mei Chen ◽  
Liting Ren ◽  
Wenya Feng ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Lung Metastasis ◽  
Transforming Growth Factor Beta ◽  
Cancer Metastasis ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Synergistic Effects ◽  
Cancer Therapeutics ◽  
Primary Tumors ◽  
Mesenchymal Transition

ABSTRACT Metastasis accounts for the majority of cancer deaths in many tumor types including breast cancer. Epithelial-mesenchymal transition (EMT) is the driving force for the occurrence and progression of metastasis, however, no targeted strategies to block the EMT program are currently available to combat metastasis. Diverse engineered nanomaterials (ENMs) have been reported to exert promising anti-cancer effects, however, no ENMs have been designed to target EMT. Palladium (Pd) nanomaterials, a type of ENM, have received substantial attention in nanomedicine due to their favorable photothermal performance for cancer therapeutics. Herein, Pd nanoplates (PdPL) were found to be preferentially biodistributed to both primary tumors and metastatic tumors. Importantly, PdPL showed a significant inhibition of lung metastasis with and without near-infrared (NIR) irradiation. Mechanistic investigations revealed that EMT was significantly compromised in breast cancer cells upon the PdPL treatment, which was partially due to the inhibition of the transforming growth factor-beta (TGF-β) signaling. Strikingly, the PdPL was found to directly interact with TGF-β proteins to diminish TGF-β functions in activating its downstream signaling, as evidenced by the reduced phosphorylation of Smad2. Notably, TGF-β-independent pathways were also involved in undermining EMT and other important biological processes that are necessary for metastasis. Additionally, NIR irradiation elicited synergistic effects on PdPL-induced inhibition of primary tumors and metastasis. In summary, these results revealed that the PdPL remarkably curbed metastasis by inhibiting EMT signaling, thereby indicating the promising potential of PdPL as a therapeutic agent for treating breast cancer metastasis.

scholarly journals Targeted inactivation of β1 integrin induces β3 integrin switching, which drives breast cancer metastasis by TGF-β

2013 ◽  
Vol 24 (21) ◽  
pp. 3449-3459 ◽  
Author(s):  
Jenny G. Parvani ◽  
Amy J. Galliher-Beckley ◽  
Barbara J. Schiemann ◽  
William P. Schiemann
Keyword(s):  
Breast Cancer ◽  
Cancer Metastasis ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Breast Cancer Metastasis ◽  
Β1 Integrin ◽  
Metastatic Progression ◽  
Breast Cancer Patients ◽  
Mesenchymal Transition ◽  
Β3 Integrin

Mammary tumorigenesis and epithelial–mesenchymal transition (EMT) programs cooperate in converting transforming growth factor-β (TGF-β) from a suppressor to a promoter of breast cancer metastasis. Although previous reports associated β1 and β3 integrins with TGF-β stimulation of EMT and metastasis, the functional interplay and plasticity exhibited by these adhesion molecules in shaping the oncogenic activities of TGF-β remain unknown. We demonstrate that inactivation of β1 integrin impairs TGF-β from stimulating the motility of normal and malignant mammary epithelial cells (MECs) and elicits robust compensatory expression of β3 integrin solely in malignant MECs, but not in their normal counterparts. Compensatory β3 integrin expression also 1) enhances the growth of malignant MECs in rigid and compliant three-dimensional organotypic cultures and 2) restores the induction of the EMT phenotypes by TGF-β. Of importance, compensatory expression of β3 integrin rescues the growth and pulmonary metastasis of β1 integrin–deficient 4T1 tumors in mice, a process that is prevented by genetic depletion or functional inactivation of β3 integrin. Collectively our findings demonstrate that inactivation of β1 integrin elicits metastatic progression via a β3 integrin–specific mechanism, indicating that dual β1 and β3 integrin targeting is necessary to alleviate metastatic disease in breast cancer patients.

scholarly journals Polyphenols Modulating Effects of PD-L1/PD-1 Checkpoint and EMT-Mediated PD-L1 Overexpression in Breast Cancer

Nutrients ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1718
Author(s):  
Samia S. Messeha ◽  
Najla O. Zarmouh ◽  
Karam F. A. Soliman
Keyword(s):  
Breast Cancer ◽  
Transforming Growth Factor Beta ◽  
Cancer Metastasis ◽  
Epithelial To Mesenchymal Transition ◽  
Antitumor Agents ◽  
Transforming Growth Factor ◽  
Close Association ◽  
Immune Surveillance ◽  
Cell Phenotype ◽  
Mesenchymal Transition

Investigating dietary polyphenolic compounds as antitumor agents are rising due to the growing evidence of the close association between immunity and cancer. Cancer cells elude immune surveillance for enhancing their progression and metastasis utilizing various mechanisms. These mechanisms include the upregulation of programmed death-ligand 1 (PD-L1) expression and Epithelial-to-Mesenchymal Transition (EMT) cell phenotype activation. In addition to its role in stimulating normal embryonic development, EMT has been identified as a critical driver in various aspects of cancer pathology, including carcinogenesis, metastasis, and drug resistance. Furthermore, EMT conversion to another phenotype, Mesenchymal-to-Epithelial Transition (MET), is crucial in developing cancer metastasis. A central mechanism in the upregulation of PD-L1 expression in various cancer types is EMT signaling activation. In breast cancer (BC) cells, the upregulated level of PD-L1 has become a critical target in cancer therapy. Various signal transduction pathways are involved in EMT-mediated PD-L1 checkpoint overexpression. Three main groups are considered potential targets in EMT development; the effectors (E-cadherin and Vimentin), the regulators (Zeb, Twist, and Snail), and the inducers that include members of the transforming growth factor-beta (TGF-β). Meanwhile, the correlation between consuming flavonoid-rich food and the lower risk of cancers has been demonstrated. In BC, polyphenols were found to downregulate PD-L1 expression. This review highlights the effects of polyphenols on the EMT process by inhibiting mesenchymal proteins and upregulating the epithelial phenotype. This multifunctional mechanism could hold promises in the prevention and treating breast cancer.

scholarly journals Obesity-Activated Lung Stromal Cells Promote Myeloid Lineage Cell Accumulation and Breast Cancer Metastasis

Cancers ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1005
Author(s):  
Lauren E. Hillers-Ziemer ◽  
Abbey E. Williams ◽  
Amanda Janquart ◽  
Caitlin Grogan ◽  
Victoria Thompson ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stromal Cells ◽  
Cancer Metastasis ◽  
Transforming Growth Factor ◽  
Breast Cancer Metastasis ◽  
Tumor Formation ◽  
Obese Mouse ◽  
Obese Mice ◽  
Myeloid Lineage ◽  
Primary Tumors

Obesity is correlated with increased incidence of breast cancer metastasis; however, the mechanisms underlying how obesity promotes metastasis are unclear. In a diet-induced obese mouse model, obesity enhanced lung metastasis in both the presence and absence of primary mammary tumors and increased recruitment of myeloid lineage cells into the lungs. In the absence of tumors, obese mice demonstrated increased numbers of myeloid lineage cells and elevated collagen fibers within the lung stroma, reminiscent of premetastatic niches formed by primary tumors. Lung stromal cells isolated from obese tumor-naïve mice showed increased proliferation, contractility, and expression of extracellular matrix, inflammatory markers and transforming growth factor beta-1 (TGFβ1). Conditioned media from lung stromal cells from obese mice promoted myeloid lineage cell migration in vitro in response to colony-stimulating factor 2 (CSF2) expression and enhanced invasion of tumor cells. Together, these results suggest that prior to tumor formation, obesity alters the lung microenvironment, creating niches conducive to metastatic growth.

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.

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