Molecular Characterization of Epithelial to Mesenchymal Transition in Human Prostatic Epithelial Cells

2010 ◽  
Vol 1 (2) ◽  
Author(s):  
Victor K. Lin ◽  
Shih-Ya Wang ◽  
Lanxiao Wu ◽  
Smitha M. Rao ◽  
J. C. Chiao ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Cancer Metastasis ◽  
Epithelial To Mesenchymal Transition ◽  
Mammary Epithelial Cells ◽  
Critical Role ◽  
Three Dimensional ◽  
Mammary Epithelial ◽  
Mesenchymal Transition ◽  
Enhanced Mobility ◽  
E Cadherin

Epithelial to mesenchymal transition (EMT) has been believed to play a critical role in cancer metastasis. TGFβ has been described as an inducer of EMT in normal mammary epithelial cells by signaling through receptor serine/threonine kinase pathways to regulate epithelial cell plasticity and invasion. In this study, we investigated the EMT cellular responses, including morphologic changes, phenotype switches, invasiveness enhancement, and cellular contraction alteration, in TGFβ stimulated human prostate normal epithelial cells (PZ-HPV-7). Migration of TGFβ treated PZ-HPV-7 cells across matrigel was measured in invasion chambers (8 μm pore size). The cells were treated with or without TGFβ (2 ng/ml) in PrEGM media for 3 days. Immunoblot assay was conducted and it was demonstrated that the induction of vimentin when stimulated by TGFβ was accompanied by a downregulation of E-cadherin, though p-cadherin level was not altered. It was also observed that there was a decrease in cytokaretin 5/6 expression associated with the downregulation of E-cadherin during the induction of EMT. In order to study the cell contraction, three-dimensional collage lattice assay was performed. It was demonstrated that TGFβ-stimulated PZ-HPV-7 cells gained contractility. Our results showed that TGFβ stimulation induced PZ-HPV-7 cells to undergo epithelial to mesenchymal transition. EMT characteristics such as acquisition of mesenchymal markers and loss of epithelial markers were evident in the induction of vimentin and downregulation of E-cadherin and cytokeratins, as well as phenotypic alterations including increased contraction and enhanced mobility were detected.

Mnt represses epithelial identity to promote Epithelial to Mesenchymal Transition

2021 ◽  
Author(s):  
Deborah P. Lavin ◽  
Leila Abassi ◽  
Mohammed Inayatullah ◽  
Vijay K. Tiwari
Keyword(s):  
Epithelial Cells ◽  
Cell Fate ◽  
Cancer Metastasis ◽  
Epithelial To Mesenchymal Transition ◽  
Mammary Epithelial Cells ◽  
Morphological Changes ◽  
Critical Role ◽  
Chromatin Accessibility ◽  
Mammary Epithelial ◽  
Mesenchymal Transition

The multi-step process of epithelial to mesenchymal transition (EMT), whereby static epithelial cells become migratory mesenchymal cells, plays a critical role during various developmental contexts, wound healing, and pathological conditions such as cancer metastasis. Despite the established function of basic helix-loop-helix (bHLH) transcription factors (TFs) in cell-fate determination, only a few have been examined for their role in EMT. Here, using transcriptome analysis of distinct stages during stepwise progression of TGFβ-induced EMT in mammary epithelial cells, we revealed distinct categories of bHLH TFs that show differential expression kinetics during EMT. Using a siRNA-mediated functional screen for bHLH TFs during EMT, we found Max network transcription repressor (MNT) to be essential for EMT in mammary epithelial cells. We show that the depletion of MNT blocks TGFβ-induced morphological changes during EMT, and this is accompanied by de-repression of a large number of epithelial genes. We show that MNT mediates the repression of epithelial identity genes during EMT by recruiting HDAC1 and mediating the loss of H3K27ac and chromatin accessibility. Lastly, we show that MNT is expressed at higher levels in EMT-High breast cancer cells and is required for their migration. Taken together, these findings establish MNT as a critical regulator of cell-fate changes during mammary EMT.

scholarly journals C-terminal domain small phosphatase-like 2 promotes epithelial-to-mesenchymal transition via Snail dephosphorylation and stabilization

Open Biology ◽  
2018 ◽  
Vol 8 (4) ◽  
pp. 170274 ◽  
Author(s):  
Yulan Zhao ◽  
Jinquan Liu ◽  
Fenfang Chen ◽  
Xin-Hua Feng
Keyword(s):  
Gene Expression ◽  
Epithelial Cells ◽  
Epithelial To Mesenchymal Transition ◽  
Mammary Epithelial Cells ◽  
Critical Role ◽  
Mesenchymal Cell ◽  
Cellular Reprogramming ◽  
Mammary Epithelial ◽  
Mesenchymal Transition ◽  
Proteasome Degradation

The epithelial-to-mesenchymal transition (EMT) is a cellular reprogramming process converting epithelial cells into mesenchymal cell morphology. Snail is a critical regulator of EMT by both suppressing epithelial gene expression and promoting mesenchymal gene expression. Expression and activity of Snail are tightly controlled at transcriptional and post-translational levels. It has previously been reported that Snail undergoes phosphorylation and ubiquitin-dependent proteasome degradation. Here, we report nuclear phosphatase SCP4/CTDSPL2 acts as a novel Snail phosphatase. SCP4 physically interacts with and directly dephosphorylates Snail. SCP4-mediated dephosphorylation of Snail suppresses the ubiquitin-dependent proteasome degradation of Snail and consequently enhances TGFβ-induced EMT. The knockdown of SCP4 in MCF10A mammary epithelial cells leads to attenuated cell migration. Collectively, our finding demonstrates that SCP4 plays a critical role in EMT through Snail dephosphorylation and stabilization.

scholarly journals The H1047R PIK3CA oncogene induces a senescence-like state, pleiotropy and acute HSP90 dependency in HER2+ mammary epithelial cells

2019 ◽  
Vol 40 (10) ◽  
pp. 1179-1190 ◽  
Author(s):  
Anindita Chakrabarty ◽  
Sreeraj Surendran ◽  
Neil E Bhola ◽  
Vishnu S Mishra ◽  
Tasaduq Hussain Wani ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Epithelial To Mesenchymal Transition ◽  
Mammary Epithelial Cells ◽  
Breast Tumors ◽  
Genetically Engineered ◽  
Mammary Epithelial ◽  
Hsp90 Inhibition ◽  
Mesenchymal Transition ◽  
Pik3ca Mutations

Abstract In pre-clinical models, co-existence of Human Epidermal Growth Factor Receptor-2 (HER2)-amplification and PI3K catalytic subunit (PIK3CA) mutations results in aggressive, anti-HER2 therapy-resistant breast tumors. This is not always reflected in clinical setting. We speculated that the complex interaction between the HER2 and PIK3CA oncogenes is responsible for such inconsistency. We performed series of biochemical, molecular and cellular assays on genetically engineered isogenic mammary epithelial cell lines and breast cancer cells expressing both oncogenes. In vitro observations were validated in xenografts models. We showed that H1047R, one of the most common PIK3CA mutations, is responsible for endowing a senescence-like state in mammary epithelial cells overexpressing HER2. Instead of imposing a permanent growth arrest characteristic of oncogene-induced senescence, the proteome secreted by the mutant cells promotes stem cell enrichment, angiogenesis, epithelial-to-mesenchymal transition, altered immune surveillance and acute vulnerability toward HSP90 inhibition. We inferred that the pleiotropism, as observed here, conferred by the mutated oncogene, depending on the host microenvironment, contributes to conflicting pre-clinical and clinical characteristics of HER2+, mutated PIK3CA-bearing tumor cells. We also came up with a plausible model for evolution of breast tumors from mammary epithelial cells harboring these two molecular lesions.

Erythropoietin Induces an Epithelial to Mesenchymal Transition-Like Process in Mammary Epithelial Cells MCF10A

2017 ◽  
Vol 118 (9) ◽  
pp. 2983-2992 ◽  
Author(s):  
Alejandra Ordoñez-Moreno ◽  
Cecilia Rodriguez-Monterrosas ◽  
Pedro Cortes-Reynosa ◽  
Julio Isael Perez-Carreon ◽  
Eduardo Perez Salazar
Keyword(s):  
Epithelial Cells ◽  
Epithelial To Mesenchymal Transition ◽  
Mammary Epithelial Cells ◽  
Mammary Epithelial ◽  
Mesenchymal Transition

scholarly journals Upregulated-flotillins and sphingosine kinase 2 derail vesicular trafic to stabilize AXL and promote epithelial-mesenchymal transition

2020 ◽  
Author(s):  
Mallory Genest ◽  
Franck Comunale ◽  
Damien Planchon ◽  
Pauline Govindin ◽  
Sophie Vacher ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Epithelial To Mesenchymal Transition ◽  
Epithelial Mesenchymal Transition ◽  
Mammary Epithelial Cells ◽  
Sphingosine Kinase ◽  
Vesicular Trafficking ◽  
Mammary Epithelial ◽  
Lipid Kinase ◽  
Mesenchymal Transition ◽  
Sphingosine Kinase 2

AbstractAltered endocytosis and vesicular trafficking are major players during tumorigenesis. Flotillin overexpression, a feature observed in many invasive tumors, and identified as a marker of poor prognosis, induces a deregulated endocytic and trafficking pathway called Upregulated Flotillin-Induced Trafficking (UFIT). Here, we found that, in non tumoral mammary epithelial cells, induction of the UFIT pathway promotes epithelial-to-mesenchymal transition (EMT) and accelerates the endocytosis of several transmembrane receptors, including AXL, in flotillin-positive late endosomes. AXL overexpression, frequently observed in cancer cells, is linked to EMT and metastasis formation. In flotillin-overexpressing non-tumoral mammary epithelial cells and in invasive breast carcinoma cells, we found that the UFIT-mediated AXL endocytosis allows its stabilization and depends on sphingosine-kinase 2, a lipid kinase recruited in flotillin-rich plasma membrane-domains and endosomes.Thus, the deregulation of vesicular trafficking following flotillin upregulation, and through sphingosine kinase 2, emerges as a new mechanism of AXL overexpression and EMT-inducing signaling pathway activation.

scholarly journals ESX induces transformation and functional epithelial to mesenchymal transition in MCF-12A mammary epithelial cells

Oncogene ◽  
2004 ◽  
Vol 23 (9) ◽  
pp. 1766-1779 ◽  
Author(s):  
Pepper J Schedin ◽  
Kristin L Eckel-Mahan ◽  
Shauntae M McDaniel ◽  
Jason D Prescott ◽  
Kelley S Brodsky ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Epithelial To Mesenchymal Transition ◽  
Mammary Epithelial Cells ◽  
Mammary Epithelial ◽  
Mesenchymal Transition

scholarly journals The Tumor Suppressor CYLD Inhibits Mammary Epithelial to Mesenchymal Transition by the Coordinated Inhibition of YAP/TAZ and TGFβ Signaling

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2047
Author(s):  
Athanasios Pseftogas ◽  
Konstantinos Xanthopoulos ◽  
Theofilos Poutahidis ◽  
Chrysanthi Ainali ◽  
Dimitra Dafou ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Transcription Factors ◽  
Tumor Suppressor ◽  
Epithelial Cells ◽  
Epithelial To Mesenchymal Transition ◽  
Mammary Epithelial Cells ◽  
Mammary Epithelial ◽  
Human Breast ◽  
Tgfβ Signaling ◽  
Mesenchymal Transition

Downregulation of the cylindromatosis (CYLD) tumor suppressor has been associated with breast cancer development and progression. Here, we report a critical role for CYLD in maintaining the phenotype of mammary epithelial cells in vitro and in vivo. CYLD downregulation or inactivation induced an epithelial to mesenchymal transition of mammary epithelial cells that was dependent on the concomitant activation of the transcription factors Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) and transforming growth factor beta (TGFβ)signaling. CYLD inactivation enhanced the nuclear localization of YAP/TAZ and the phosphorylation of Small Mothers Against Decapentaplegic (SMAD)2/3 proteins in confluent cell culture conditions. Consistent with these findings were the hyperplastic alterations of CYLD-deficient mouse mammary epithelia, which were associated with enhanced nuclear expression of the YAP/TAZ transcription factors. Furthermore, in human breast cancer samples, downregulation of CYLD expression correlates with enhanced YAP/TAZ-regulated target gene expression. Our results identify CYLD as a critical regulator of a signaling node that prevents the coordinated activation of YAP/TAZ and the TGFβ pathway in mammary epithelial cells, in order to maintain their phenotypic identity and homeostasis. Consequently, they provide a novel conceptual framework that supports and explains a causal implication of deficient CYLD expression in aggressive human breast cancers.

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