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Elf5 inhibits epithelial mesenchymal transition in development and cancer metastasis through transcriptional repression of Snail2

ABSTRACT: Elf5 (or ESE-2) is an ETS transcription factor that is abundantly expressed in the mammary epithelium, where it plays a critical role in dictating cell fate and lineage choices. These changes are in part mediated by alterations in the expression and activity of critical components of the Jak/Stat pathway. While the biological function of Elf5 in mammary gland development has been well characterized, its role in breast cancer remains to be elucidated. Here we show that loss of Elf5 leads to features associated with epithelial-mesenchymal transition (EMT) in the mouse mammary gland during pregnancy and lactation. These cellular changes in Elf5-null mammary epithelia are also reflected at the molecular level by the global enrichment of EMT-related gene signatures. ELF5 is expressed in higher level in weakly metastatic breast cancer cells that retained epithelial features compared to highly metastatic cells with mesenchymal features. ELF5 knockdown in T47D breast cancer cells resulted in EMT and increased migration. Conversely, ectopic expression of Elf5 revert mesenchymal-like MDA-MB-231 cells and its lung-tropic variant LM2 to an epithelial phenotype, with reduced migration, invasion and lung metastatic abilities. Finally, we showed that Elf5 binds directly to the promoter of the EMT transcriptional factor Snail2 (Slug) and repress its expression. Taken together, these data established a novel function for Elf5 in inhibiting EMT in normal mammary epithelium and in breast cancer through direct targeting of Snail2. This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE32150 | GEO | 2012/09/20

SECONDARY ACCESSION(S): PRJNA147651

REPOSITORIES: GEO

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Elf5 inhibits epithelial mesenchymal transition in development and cancer metastasis through transcriptional repression of Snail2

Project description:Elf5 (or ESE-2) is an ETS transcription factor that is abundantly expressed in the mammary epithelium, where it plays a critical role in dictating cell fate and lineage choices. These changes are in part mediated by alterations in the expression and activity of critical components of the Jak/Stat pathway. While the biological function of Elf5 in mammary gland development has been well characterized, its role in breast cancer remains to be elucidated. Here we show that loss of Elf5 leads to features associated with epithelial-mesenchymal transition (EMT) in the mouse mammary gland during pregnancy and lactation. These cellular changes in Elf5-null mammary epithelia are also reflected at the molecular level by the global enrichment of EMT-related gene signatures. ELF5 is expressed in higher level in weakly metastatic breast cancer cells that retained epithelial features compared to highly metastatic cells with mesenchymal features. ELF5 knockdown in T47D breast cancer cells resulted in EMT and increased migration. Conversely, ectopic expression of Elf5 revert mesenchymal-like MDA-MB-231 cells and its lung-tropic variant LM2 to an epithelial phenotype, with reduced migration, invasion and lung metastatic abilities. Finally, we showed that Elf5 binds directly to the promoter of the EMT transcriptional factor Snail2 (Slug) and repress its expression. Taken together, these data established a novel function for Elf5 in inhibiting EMT in normal mammary epithelium and in breast cancer through direct targeting of Snail2. This SuperSeries is composed of the following subset Series: GSE32143: LM2 cell: infected with lentivirus to stably express Elf5 vs GFP GSE32144: MDA-MB-231 cell: infected with lentivirus to stably express mut-Elf5 vs WT-Elf5

2012-09-20 | E-GEOD-32150 | biostudies-arrayexpress

Mammary morphogenesis and regeneration require the inhibition of EMT at terminal end buds by Ovol2 transcriptional repressor

Project description:Epithelial cells possess remarkable plasticity, having the ability to become mesenchymal cells through alterations in adhesion and motility (epithelial-to-mesenchymal transition or EMT). However, it is still unknown whether and how epithelial plasticity is kept in check in epithelial cells during development. Here we show that restricting the EMT of mammary epithelial cells by transcription factor Ovol2 is required for proper morphogenesis and regeneration. Deletion of Ovol2 blocks mammary ductal morphogenesis, depletes stem/progenitor cell reservoirs, and leads epithelial cells to undergo EMT in vivo to become non-epithelial cell types. Ovol2 directly represses myriad EMT inducers and its absence switches response to TGF-beta from growth arrest to EMT. Furthermore, forced expression of the repressor isoform of Ovol2 is able to reprogram metastatic breast cancer cells from a mesenchymal to an epithelial state. Our findings underscore the critical importance of exquisitely regulating epithelial plasticity in development and cancer. Refer to individual Series

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SWI/SNF Chromatin-Remodeling Factor Smarcd3/Baf60c Controls Epithelial-Mesenchymal Transition by Inducing Wnt5a Signaling

Project description:We previously identified a gene signature predicted to regulate the epithelial-mesenchymal transition (EMT) in both epithelial tissue stem cells and breast cancer cells. A phenotypic RNA interference (RNAi) screen identified the genes within this 140-gene signature that promoted the conversion of mesenchymal epithelial cell adhesion molecule-negative (EpCAM-) breast cancer cells to an epithelial EpCAM+/high phenotype. The screen identified 10 of the 140 genes whose individual knockdown was sufficient to promote EpCAM and E-cadherin expression. Among these 10 genes, RNAi silencing of the SWI/SNF chromatin-remodeling factor Smarcd3/Baf60c in EpCAM- breast cancer cells gave the most robust transition from the mesenchymal to epithelial phenotype. Conversely, expression of Smarcd3/Baf60c in immortalized human mammary epithelial cells induced an EMT. The mesenchymal-like phenotype promoted by Smarcd3/Baf60c expression resulted in gene expression changes in human mammary epithelial cells similar to that of claudin-low triple-negative breast cancer cells. These mammary epithelial cells expressing Smarcd3/Baf60c had upregulated Wnt5a expression. Inhibition of Wnt5a by either RNAi knockdown or blocking antibody reversed Smarcd3/Baf60c-induced EMT. Thus, Smarcd3/Baf60c epigenetically regulates EMT by activating WNT signaling pathways. sampleXreference

2013-08-19 | E-GEOD-40145 | biostudies-arrayexpress

Mammary morphogenesis and regeneration require the inhibition of EMT at terminal end buds by Ovol2 transcriptional repressor

2014-03-19 | GSE54126 | GEO

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Project description:Claudin-low breast cancer represents an aggressive molecular subtype that is comprised of mostly triple-negative mammary tumor cells that possess stem cell-like and mesenchymal features. Little is known about the cellular origin and oncogenic drivers that promote claudin-low breast cancer. In this study, we show that persistent oncogenic RAS signaling causes highly metastatic triple-negative mammary tumors in mice. More importantly, the activation of endogenous mutant KRAS and expression of exogenous KRAS specifically in luminal epithelial cells in a continuous and differentiation stage-independent manner induces preneoplastic lesions that evolve into basal-like and claudin-low mammary cancers. Further investigations demonstrate that the continuous signaling of oncogenic RAS as well as regulators of EMT play a crucial role in the cellular plasticity and maintenance of the mesenchymal and stem cell characteristics of claudin-low mammary cancer cells.

2021-05-05 | GSE157333 | GEO

Transcription profiling of mouse BALB/c strain animals injected with breast cancer 4T1-derived cells to investigate the role of epithelial to mesenchymal transition (EMT) in spontaneous breast cancer metastasis

Project description:Epithelial-mesenchymal transition (EMT) has been linked to cancer progression and metastatic propensity. The 4T1 tumor is a clinically relevant model of spontaneous breast cancer metastasis. Here we characterize 4T1-derived cell lines for EMT, in vitro invasiveness and in vivo metastatic ability. Contrary to expectations, the 67NR cells, which form primary tumors but fail to metastasize, express vimentin and N-cadherin, but not E-cadherin. 4T1 cells, however, express E-cadherin, are highly migratory and invasive, and metastasize to multiple sites. The 66cl4 metastatic cells display mixed epithelial and mesenchymal markers, but are less migratory and invasive than 67NR cells. These findings demonstrate that the metastatic ability of breast cancer cells does not correlate with genotypic and phenotypic properties of EMT per se, and suggest that other processes may govern metastatic capability. Gene expression analysis also has not identified differences in EMT markers, but has identified several candidate genes that may influence metastatic ability. Experiment Overall Design: Female BALB/c mice were injected with 1x10^6 viable cells (3 mice with 4T1/CMVLUC, 3 mice with 66cl4/CMVLUC, and 3 mice with 67NR/CMVLUC) into the right fourth mammary gland. 15 days after injection primary tumors were excised, and total RNA for microarray hybridization was isolated from the tumor part of laser capture microdissected sections.

2009-03-07 | E-GEOD-11259 | biostudies-arrayexpress

SWI/SNF Chromatin-Remodeling Factor Smarcd3/Baf60c Controls Epithelial-Mesenchymal Transition by Inducing Wnt5a Signaling

2013-08-19 | GSE40145 | GEO

Poorly metastatic HCT116 vs metastatic E1 colon cancer cell lines

Project description:Comparison of gene expression between poorly metastatic HCT116 colon cancer cell line and the in-vivo derived metastatic E1 cell line, which has EMT (epithelial to mesenchymal transition) features. Each cell line has triplicate chips.

2011-03-01 | E-GEOD-13759 | biostudies-arrayexpress

Obesity Promotes Epithelial-To-Mesenchymal Transition and Tumor Progression in a Mouse Model of Claudin-Low Breast Cancer.

Project description:ABSTRACT: Obesity is responsible for decreased overall survival for breast cancer patients. Here, we describe the generation, characterization and application of a novel murine mammary tumor initiating cell model (M-Wnt) that recapitulates the claudin-low subtype of human breast cancer and permits the study of TIC’s in wild-type, immunocompetent mice. M-Wnt cells readily form mammospheres in suspension culture, express markers consistent with epithelial-to-mesenchymal transition (EMT), and generate claudin-low mammary tumors when as few as 50 cells are orthotopically injected. Using the M-Wnt cell lines in tandem with a more basal-like epithelial breast cancer cell line, E-Wnt, we found that diet induced obesity significantly downregulates epithelial markers, such as E-cadherin, and upregulates mesenchymal markers including fibronectin, N-cadherin, SNAIL, Oct-4, and TGF-b. This reveals a previously unidentified link between energy balance and EMT. The ability of calorie restriction (CR) to reverse EMT, upregulate epithelial markers and downregulate mesenchymal markers indicates the plasticity of the TICs, as well as the potential importance of lifestyle modifications as cancer prevention strategies. 28 array samples

2012-06-29 | E-GEOD-28713 | biostudies-arrayexpress

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