Abstract P5-05-04: E-Cadherin and Its Proteolytic Fragments Trump Epithelial-Mesenchymal Transition and Function as Dominant Oncogenes in Inflammatory Breast Cancer

2010 ◽  
Author(s):  
SH Barsky ◽  
Y Ye ◽  
Y Xiao ◽  
K. Yearsley
Keyword(s):  
Breast Cancer ◽  
Inflammatory Breast Cancer ◽  
Epithelial Mesenchymal Transition ◽  
Mesenchymal Transition ◽  
And Function ◽  
E Cadherin

scholarly journals Distinct Ring1b complexes defined by DEAD-box helicases and EMT transcription factors synergistically enhance E-cadherin silencing in breast cancer

2021 ◽  
Vol 12 (2) ◽  
Author(s):  
Yawei Wang ◽  
Yingying Sun ◽  
Chao Shang ◽  
Lili Chen ◽  
Hongyu Chen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Transcription Factors ◽  
Cancer Cells ◽  
Epithelial Mesenchymal Transition ◽  
Epigenetic Mechanism ◽  
Regulation Mechanism ◽  
Rna Helicases ◽  
Mesenchymal Transition ◽  
Dead Box ◽  
E Cadherin

AbstractRing1b is a core subunit of polycomb repressive complex 1 (PRC1) and is essential in several high-risk cancers. However, the epigenetic mechanism of Ring1b underlying breast cancer malignancy is poorly understood. In this study, we showed increased expression of Ring1b promoted metastasis by weakening cell–cell adhesions of breast cancer cells. We confirmed that Ring1b could downregulate E-cadherin and contributed to an epigenetic rewiring via PRC1-dependent function by forming distinct complexes with DEAD-box RNA helicases (DDXs) or epithelial-mesenchymal transition transcription factors (EMT TFs) on site-specific loci of E-cadherin promoter. DDXs-Ring1b complexes moderately inhibited E-cadherin, which resulted in an early hybrid EMT state of epithelial cells, and EMT TFs-Ring1b complexes cooperated with DDXs-Ring1b complexes to further repress E-cadherin in mesenchymal-like cancer cells. Clinically, high expression of Ring1b with DDXs or EMT TFs predicted low levels of E-cadherin, metastatic behavior, and poor prognosis. These findings provide an epigenetic regulation mechanism of Ring1b complexes in E-cadherin expression. Ring1b complexes may be potential therapeutic targets and biomarkers for diagnosis and prognosis in invasion breast cancer.

scholarly journals 925 Utilizing multiplex immunofluorescence to explore the epithelial-mesenchymal transition in breast, ovarian cancers

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A970-A970
Author(s):  
Danielle Fails ◽  
Michael Spencer
Keyword(s):  
Breast Cancer ◽  
Invasive Ductal Carcinoma ◽  
Poor Prognosis ◽  
Epithelial Mesenchymal Transition ◽  
Ductal Carcinoma ◽  
Beta Catenin ◽  
Mesenchymal Transition ◽  
Cell Counts ◽  
Grade Ii ◽  
E Cadherin

BackgroundEpithelial-mesenchymal transition (EMT) is instrumental during embryonic development—assisting in extensive movement and differentiation of cells. However, during metastasis and tumorigenesis, this process is hijacked. The disruption of this developmental process, and subsequent acquisition of a mesenchymal phenotype, has been shown to increase therapeutic resistance and often leads to poor prognosis in breast cancer.1 Using bioinformatic resources and current clinical data, we designed a panel of biomarkers of value to specifically observe this epithelial/mesenchymal transition.MethodsHuman breast cancer FFPE tissue samples were stained with Bethyl Laboratories IHC-validated primary antibodies, followed by Bethyl HRP-conjugated secondary antibodies, and detected using Akoya Opal™ Polaris 7-color IHC kit fluorophores (Akoya Biosciences [NEL861001KT]). The panel consisted of beta-Catenin, E-Cadherin, Ki67, CD3e, PD-L1, and FOXP3. Antibody staining order was optimized using tissue microarray serial sections, three slides per target, and stained in either the first, third, or sixth position via heat-induced epitope retrieval (HIER) methods. Exposure time was maintained for all three slides/target and cell counts, signal intensity, background, and autofluorescence were analyzed. The final optimized order was then tested on the breast cancer microarray in seven-color mIF. Whole slide scans were generated using the Vectra Polaris® and analyses performed using InForm® and R® Studio.ResultsTwo integral EMT targets, E-Cadherin and beta-Catenin, were used to observe a key occurrence in this transition. Under tumorigenic circumstances, when released from the complex they form together (E-cadherin-B-catenin complex), Beta-catenin can induce EMT. This disjunction/activation of EMT can be seen in the invasive ductal carcinoma below (figure 1).The disorganized E-cadherin cells are in direct contrast to normal, non-cancerous cells in similar tissue. Total CD3e cell counts were down (2%), with 35% cells restricted to the stroma vs. the 1% seen intra-tumorally. Coupled with the elevated presence of Ki67 (10%), a level of rapid cancer growth and potential metastasis (Invasive Ductal Carcinoma Grade II) can be observed.Abstract 925 Figure 1Invasive ductal carcinoma, grade II stained with a 6-plex mIF panel designed to show the epithelial-mesenchymal transitionConclusionsThe presence of EMT in breast cancers is often indicative of a poor prognosis, so the need for reliable markers is imperative. E-Cadherin and beta-Catenin are both up-and-coming clinical targets that can serve to outline this transition within the tumor microenvironment. By utilizing these markers in mIF, closer spatial examination of proteins of interest can be achieved. The application of this mIF panel has the potential to provide invaluable insights into how tumor infiltrating lymphocytes behave in cancers exhibiting the hallmarks of EMT.AcknowledgementsWe would like to acknowledge Clemens Deurrschmid, PhD, Technical Applications Scientist Southeast/South Central, Akoya Biosciences for his assistance with image analysis.ReferencesHorne HN, Oh H, Sherman ME, et al. E-cadherin breast tumor expression, risk factors and survival: pooled analysis of 5,933 cases from 12 studies in the breast cancer association consortium. Sci Rep 2018;8:6574.

scholarly journals Baicalein inhibits fibronectin-induced epithelial–mesenchymal transition by decreasing activation and upregulation of calpain-2

2019 ◽  
Vol 10 (5) ◽  
Author(s):  
Yan Chen ◽  
Lin Chen ◽  
Duanyang Hong ◽  
Zongyue Chen ◽  
Jingyu Zhang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Extracellular Matrix ◽  
Cellular Response ◽  
Matrix Protein ◽  
Epithelial Mesenchymal Transition ◽  
T Antigen ◽  
Extracellular Matrix Protein ◽  
Mesenchymal Transition ◽  
Calpain 2 ◽  
E Cadherin

AbstractThe extracellular matrix protein fibronectin (FN) facilitates tumorigenesis and the development of breast cancer. Inhibition of the FN-induced cellular response is a potential strategy for breast cancer treatment. In the present study, we investigated the effects of the flavonoid baicalein on FN-induced epithelial–mesenchymal transition (EMT) in MCF-10A breast epithelial cells and in a transgenic mouse MMTV-polyoma middle T antigen breast cancer model (MMTV-PyMT). Baicalein inhibited FN-induced migration, invasion, and F-actin remodeling. Baicalein also suppressed FN-induced downregulation of the epithelial markers E-cadherin and ZO-1 and upregulation of the mesenchymal markers N-cadherin, vimentin, and Snail. Further investigation revealed that calpain-2 was involved in baicalein suppression of FN-induced EMT. Baicalein significantly decreased FN-enhanced calpain-2 expression and activation by suppressing its plasma membrane localization, substrate cleavage, and degradation of its endogenous inhibitor calpastatin. Overexpression of calpain-2 in MCF-10A cells by gene transfection partially blocked the inhibitory effect of baicalein on FN-induced EMT changes. In addition, baicalein inhibited calpain-2 by decreasing FN-increased intracellular calcium ion levels and extracellular signal-regulated protein kinases activation. Baicalein significantly decreased tumor onset, growth, and pulmonary metastasis in a spontaneous breast cancer MMTV-PyMT mouse model. Baicalein also reduced the expression of FN, calpain-2, and vimentin, but increased E-cadherin expression in MMTV-PyMT mouse tumors. Overall, these results revealed that baicalein markedly inhibited FN-induced EMT by inhibiting calpain-2, thus providing novel insights into the pharmacological action and mechanism of baicalein. Baicalein may therefore possess therapeutic potential for the treatment of breast cancer though interfering with extracellular matrix–cancer cell interactions.

scholarly journals RNF20 Is Critical for Snail-Mediated E-Cadherin Repression in Human Breast Cancer

2020 ◽  
Vol 10 ◽  
Author(s):  
Danping Wang ◽  
Yifan Wang ◽  
Xuebiao Wu ◽  
Xiangxing Kong ◽  
Jun Li ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Colony Formation ◽  
Human Breast Cancer ◽  
Epithelial Mesenchymal Transition ◽  
Epigenetic Modification ◽  
Dependent Manner ◽  
Human Breast ◽  
Mesenchymal Transition ◽  
E Cadherin

BackgroundE-cadherin, a hallmark of epithelial-mesenchymal transition (EMT), is often repressed due to Snail-mediated epigenetic modification; however, the exact mechanism remains unclear. There is an urgent need to understand the determinants of tumor aggressiveness and identify potential therapeutic targets in breast cancer.Experimental designWe studied the association of RNF20 with Snail and G9a by co-immunoprecipitation. We employed quantitative real-time PCR, ChIP, transwell assay, colony formation assay, and mammosphere assay to dissect the molecular events associated with the repression of E-cadherin in human breast cancer. We used a proteogenomic dataset that contains 105 breast tumor samples to determine the clinical relevance of RNF20 by Kaplan-Meier analyses.ResultsIn this study, we identified that Snail interacted with RNF20, an E3 ubiquitin-protein ligase responsible for monoubiquitination of H2BK120, and G9a, a methyltransferase for H3K9me2. RNF20 expression led to the inhibition of E-cadherin expression in the human breast cancer cells. Mechanically, we showed that RNF20 and H3K9m2 were enriched on the promoter of E-cadherin and knockdown of Snail reduced the enrichment of RNF20, showing a Snail-dependent manner. RNF20 expression enhanced breast cancer cell migration, invasion, tumorsphere and colony formation. Clinically, patients with high RNF20 expression had shorter overall survival.ConclusionRNF20 expression contributes to EMT induction and breast cancer progression through Snail-mediated epigenetic suppression of E-cadherin expression, suggesting the importance of RNF20 in breast cancer.

scholarly journals Epithelial-Mesenchymal Transition Markers in Breast Cancer and Pathological Responseafter Neoadjuvant Chemotherapy

2018 ◽  
Vol 12 ◽  
pp. 117822341878807 ◽  
Author(s):  
Shaimaa Elzamly ◽  
Nabeel Badri ◽  
Osvaldo Padilla ◽  
Alok Kumar Dwivedi ◽  
Luis A Alvarado ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Neoadjuvant Chemotherapy ◽  
Epithelial Mesenchymal Transition ◽  
Pathologic Complete Response ◽  
Inverse Correlation ◽  
Immunohistochemical Analysis ◽  
Wilcoxon Test ◽  
Fisher Exact Test ◽  
Mesenchymal Transition ◽  
E Cadherin

The association between pathologic complete response (pCR) following to neoadjuvant chemotherapy (NAC) and the improved survival in breast cancer has been previously reported. The aim of this study was is to explore the expression of several biomarkers described during epithelial-mesenchymal transition (EMT) and the achievement of pCR in different molecular subtypes of breast cancer. We identified archived pathology tissue from patients with breast cancer who received NAC during the year 2014. We performed immunohistochemical analysis of vimentin, nuclear factor κB (NF-κB), epidermal growth factor receptor (EGFR), E-cadherin, estrogen receptor (ER), progesterone receptor, and Her2neu and studied the association between the expression of these markers and pCR. A Fisher exact test for categorical cofactors, an unpaired t test and a nonparametric Wilcoxon test for continuous cofactors were used. The results showed a significant expression of vimentin in triple-negative breast cancer (TNBC; P = .023). An inverse correlation between vimentin and the ER expression ( P = .032) was observed. No significant association was noted for vimentin, NF-κB, EGFR, and E-cadherin was associated with pCR. This study suggests that the evaluated EMT related biomarkers are not associated with pCR after NAC chemotherapy in an unselected breast cancer population. Vimentin and NF-κB expressions were associated with TNBC and could be further explored as potential therapeutic targets in this subgroup. A prevalence of vimentin and NF-κB among Hispanic patients with breast cancer warrants further investigation as a possibly contributing to the prevalence of TNBC and adverse prognosis in this population.

scholarly journals Actinomycin V Inhibits Migration and Invasion via Suppressing Snail/Slug-Mediated Epithelial-Mesenchymal Transition Progression in Human Breast Cancer MDA-MB-231 Cells In Vitro

Marine Drugs ◽  
2019 ◽  
Vol 17 (5) ◽  
pp. 305 ◽  
Author(s):  
Shiqi Lin ◽  
Caiyun Zhang ◽  
Fangyuan Liu ◽  
Jiahui Ma ◽  
Fujuan Jia ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Human Breast Cancer ◽  
Actinomycin D ◽  
Epithelial Mesenchymal Transition ◽  
Migration And Invasion ◽  
Human Breast ◽  
Mesenchymal Transition ◽  
Expression Levels ◽  
E Cadherin

Actinomycin V, an analog of actinomycin D produced by the marine-derived actinomycete Streptomyces sp., possessing a 4-ketoproline instead of a 4-proline in actinomycin D. In this study, the involvement of snail/slug-mediated epithelial-mesenchymal transition (EMT) in the anti-migration and -invasion actions of actinomycin V was investigated in human breast cancer MDA-MB-231 cells in vitro. Cell proliferation effect was evaluated by 3-(4,5-Dimethylthiazol)-2,5-diphenyltetrazolium bromide (MTT) assay. Wound-healing and Transwell assay were performed to investigate the anti-migration and -invasion effects of actinomycin V. Western blotting was used to detect the expression levels of E-cadherin, N-cadherin, vimentin, snail, slug, zinc finger E-box binding homeobox 1 (ZEB1), and twist proteins and the mRNA levels were detected by rt-PCR. Actinomycin V showed stronger cytotoxic activity than that of actinomycin D. Actinomycin V up-regulated both of the protein and mRNA expression levels of E-cadherin and down-regulated that of N-cadherin and vimentin in the same cells. In this connection, actinomycin V decreased the snail and slug protein expression, and consequently inhibited cells EMT procession. Our results suggest that actinomycin V inhibits EMT-mediated migration and invasion via decreasing snail and slug expression, which exhibits therapeutic potential for the treatment of breast cancer and further toxicity investigation in vivo is needed.

scholarly journals The effect of Angelica dahurica extract on breast carcinogenesis in mouse

2020 ◽  
Author(s):  
Ruihong Zhang ◽  
Teng Liu ◽  
Xiangli Zhang ◽  
Yuan Liu
Keyword(s):  
Breast Cancer ◽  
Mouse Model ◽  
Signaling Pathways ◽  
Breast Tissue ◽  
Epithelial Mesenchymal Transition ◽  
Angelica Dahurica ◽  
Mesenchymal Transition ◽  
Stat Signaling ◽  
E Cadherin

IntroductionAngelica dahurica extract (ADE) has been demonstrated to possess functions of immune response modulation, breast injury and fibrosis amelioration, breast regeneration regulation, and suppression of breast cancer.Material and methodsTo explore the effect of the ADE on breast cancer generation and epithelial-mesenchymal transition (EMT) in vivo, a breast cancer mouse model was established. Chinese traditional medicine ADE was administered to mice bearing breast cancer, which were randomly divided into a negative group, ADE group (two doses), and model group. The breast tissue of the mouse model was fixed and H&E staining was performed for subsequent histological observation. Immunofluorescence assay and immunohistochemical staining were performed to examine the breast cancer related proteins, SNCG and BCRP in breast tissue; Western blotting and quantitative real-time polymerase chain reaction (PCR) were performed to detect proteins and gene expression of epithelial-mesenchymal transition (EMT)-related markers, E-cadherin, N-cadherin, vimentin, transforming growth factor  (TGF-), and SNAIL, as well as signals in the MAPK and JAK/STAT signaling pathways.ResultsPathological manifestation of breast tissues in ADE-treated mouse was clearly reduced in both visual inspection and H&E staining. Breast cancer specific SNCG and BCRP expression significantly decreased after ADE administration. Furthermore, increased E-cadherin and decreased N-cadherin, vimentin, SNAIL and TGF- expression might be associated with the anti-EMT property of ADE. Both MAPK and JAK/STAT signaling pathways were observed to be inactivated after ADE treatment.ConclusionsCollectively, the evidence showed that ADE restrained breast cancer development in vivo through blocking the EMT process, probably by down-regulation of MAPK and JAK/STAT signaling pathways.

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