• biomarkers
• castration-resistant prostate cancer
• circulating tumor cells
• microfluidics
• tumor-on-a-chip

• Male
• Animals
• Humans
• Prostatic Neoplasms, Castration-Resistant/drug therapy
• Microfluidics
• Tumor Microenvironment

• 06465-14 Natural Sciences and Engineering Research Council

• Cancer
• Cell signaling
• EpCAM
• Extracellular vesicles
• Immune
• Therapy

• 81874065 National Natural Science Foundation of China
• 81372327 National Natural Science Foundation of China
• 2020YQ05 Tongji Hospital (HUST) Foundation for Excellent Young Scientists
• 2018ZX10723204-003-003 State Key Project on Infectious Diseases of China
• 2018YFA0208904 National Key Research and Development Program of China
• 2018ACA137 Major Technological Innovation Projects of Hubei Province
• 2020YFA0710700 National Basic Research Program of China

N‐α‐Acetyltransferase 10 (NAA10) was reported to be involved in tumour invasion and metastasis in several of tumours. However, the role and mechanism of NAA10‐mediated invasion and metastasis in oral squamous cell carcinoma (OSCC) remains undetermined. Herein, our study showed that NAA10 inhibits cell migration and invasion in vitro and attenuates the xenograft tumorigenesis in nude mice. Mechanistically, we demonstrated that there is a physical interaction between NAA10 and RelA/p65 in OSCC cells, thereby preventing RelA/p65‐mediated transcriptional activation of Pirh2. Consequently, inhibition of Pirh2 increased p53 level and suppressed the expression of p53 downstream targets, matrix metalloprotein‐2 (MMP‐2) and MMP‐9. Therefore, NAA10 may function as a tumour metastasis suppressor in the progression of OSCC by targeting Pirh2‐p53 axis and might be a prognostic marker as well as a therapeutic target for OSCC.

• NAA10
• OSCC
• Pirh2-p53
• invasion
• metastasis

• Albumins
• Aptamers, Nucleotide/chemistry
• Humans
• SELEX Aptamer Technique

• National Science Foundation of China

• Cancer
• Cell biology
• Stem cells research

• SQLE
• cell proliferation
• cholesterol
• p53

Epithelial cell adhesion molecule (EpCAM) is a transmembrane glycoprotein expressed in epithelial tissues. EpCAM forms intercellular, homophilic adhesions, modulates epithelial junctional protein complex formation, and promotes epithelial tissue homeostasis. EpCAM is a target of molecular therapies and plays a prominent role in tumor biology. In this review, we focus on the dynamic regulation of EpCAM expression during epithelial-to-mesenchymal transition (EMT) and the functional implications of EpCAM expression on the regulation of EMT. EpCAM is frequently and highly expressed in epithelial cancers, while silenced in mesenchymal cancers. During EMT, EpCAM expression is downregulated by extracellular signal-regulated kinases (ERK) and EMT transcription factors, as well as by regulated intramembrane proteolysis (RIP). The functional impact of EpCAM expression on tumor biology is frequently dependent on the cancer type and predominant oncogenic signaling pathways, suggesting that the role of EpCAM in tumor biology and EMT is multifunctional. Membrane EpCAM is cleaved in cancers and its intracellular domain (EpICD) is transported into the nucleus and binds β-catenin, FHL2, and LEF1. This stimulates gene transcription that promotes growth, cancer stem cell properties, and EMT. EpCAM is also regulated by epidermal growth factor receptor (EGFR) signaling and the EpCAM ectoderm (EpEX) is an EGFR ligand that affects EMT. EpCAM is expressed on circulating tumor and cancer stem cells undergoing EMT and modulates metastases and cancer treatment responses. Future research exploring EpCAM’s role in EMT may reveal additional therapeutic opportunities.

• cancer stem cells (CSCs)
• circulating tumor cells (CTCs)
• epithelial cancers
• epithelial cell adhesion molecule (EpCAM)
• epithelial-to-mesenchymal transition (EMT)
• metastasis

• Epithelial cell adhesion molecule
• Metastasis
• TACSD
• Trop2

• Gleason score
• biomarkers
• functional validation
• metabolism
• prostate cancer

• Cell Line, Tumor
• Disease Progression
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic
• Humans
• Male
• Neoplasm Grading
• Prostate/pathology
• Prostatic Neoplasms/genetics
• Prostatic Neoplasms/pathology

• Aerobic glycolysis
• Breast cancer
• Key enzymes
• Signaling pathways
• Transcription factors

• cell adhesion
• cell signaling
• epithelial cell adhesion molecule (EpCAM)
• gamma-secretase
• live-cell imaging
• proteasome degradation
• protein processing
• proteolytic processing
• regulated intramembrane proteolysis
• sheddase
• transmembrane protein

Gelatinous drop-like corneal dystrophy (GDLD) is a rare autosomal recessive corneal dystrophy that causes severe vision loss. Because of its poor prognosis, there is a demand for novel treatments for GDLD. Here, we establish a new in vitro disease model of GDLD based on immortalized human corneal epithelial (HCE-T) cells.

By using transcription activator-like effector nuclease plasmids, tumor-associated calcium signal transducer 2 (TACSTD2) and its paralogous gene, epithelial cell adhesion molecule (EpCAM), were knocked out in HCE-T cells. Fluorescence-activated cell sorting was performed to obtain cells in which both TACSTD2 and EpCAM were knocked out (DKO cells). In DKO cells, the expression levels and subcellular localizations of claudin (CLDN) 1, 4, and 7, and ZO-1 were investigated, along with epithelial barrier function. By using DKO cells, the feasibility of gene therapy for GDLD was also investigated.

DKO cells exhibited decreased expression and aberrant subcellular localization of CLDN1 and CLDN7 proteins, as well as decreased epithelial barrier function. Transduction of the TACSTD2 gene into DKO cells nearly normalized expression levels and subcellular localization of CLDN1 and CLDN7 proteins, while significantly increasing epithelial barrier function.

We established an in vitro disease model of GDLD by knocking out TACSTD2 and its paralogous gene, EpCAM, in HCE-T cells. This cell line accurately reflected pathological aspects of GDLD.

We expect that the cell line will be useful to elucidate the pathogenesis of GDLD and develop novel treatments for GDLD.

• EpCAM
• TACSTD2
• claudin, tight junction
• gelatinous drop-like corneal dystrophy

Locally advanced head and neck squamous cell carcinomas (HNSCC) have limited prognosis due to frequent treatment failure. Currently, TNM-classification and human papillomavirus (HPV) infection are the sole clinical prognosticators of outcome. Tumor heterogeneity and stemness based on epithelial-mesenchymal-transition reportedly associate with therapy resistance. The capacity of epithelial marker EpCAM (EpEX), stemness regulator Sox2 and mesenchymal marker vimentin to predict clinical outcome of HSNCC patients was assessed upon immunohistochemistry staining in two cohorts of HNSCC patients treated with surgery and adjuvant radio (chemo) therapy (n = 94) and primary radio (chemo) therapy (n = 94), respectively. Prognostic values with respect to overall, disease-free and disease-specific survival were assessed in uni- and multivariate cox proportional hazard models to generate integrated risk scores. EpEX, Sox2 and vimentin displayed substantial inter- and intratumoral heterogeneity. EpEX^high and Sox2^high predicted improved clinical outcome in the discovery cohort and in the HPV-negative sub-cohort. EpEX^high and Sox2^high were confirmed as prognosticators of clinical outcome in the validation cohort treated with definitive radio(chemo)therapy. Importantly, EpEX^high identified patients with improved survival within the HPV-negative subgroup of the validation cohort. Hence, Sox2^high and particularly EpEX^high have potential as tools to predict clinical performance of HNSCC patients, foremost HPV-negative cases, in the frame of molecular-guided treatment decision-making.

It is known that Cancer Associated Fibroblast (CAFs) from the primary tumor site can accompany cancer cells to a secondary site during the process of metastasis. We hypothesize that these CAFs could be transformed to an altered cell type, which can be called as Metastasis Associated Fibroblasts (MAF) in turn can support, and convoy cancer cells for metastasis. There are no published reports that have characterized and distinguished CAFs from MAF. It is well established that some of the cancer cells within the tumor mass accumulate novel mutations prior to metastasis. Hence, we speculated that mutations in the tumor suppressor gene, BRCA1, which is already reported to induce metastasis via abnormal expression of Ezrin, Radixin and Moesin (ERM), could generate MAF. In the present study, we demonstrate for the first time that CAFs isolated from primary breast cancer tissues when co-cultured with BRCA1 mutated HCC1937 cells transform CAFs to MAF in vitro. As expected, MAF augmented proliferation, migration and invasion along with over-expression of epithelial mesenchymal transition (EMT) markers, Ezrin and CCL5, thereby facilitating metastasis. Therefore, we inhibited Ezrin and CCL5 in vitro in MAF and observed that the migration and invasion abilities of these cells were attenuated. This highlights the intriguing possibilities of combination therapy using MAF inhibitors as anti-metastatic agents along with anticancer drugs, to control the metastatic spread from primary tumor site.

• CTCs
• DTCs
• EpCAM
• MICs
• metastases

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy. Here we show that shotgun and targeted protein sequencing can be used to identify potential prognostic biomarkers in formalin-fixed paraffin-embedded specimens from 9 patients with PDAC with “short” survival (<12 months) and 10 patients with “long” survival (>45 months) undergoing surgical resection. A total of 24 and 147 proteins were significantly upregulated [fold change ≥2 or ≤0.5 and P<0.05; or different detection frequencies (≥5 samples)] in patients with “short” survival (including GLUT1) and “long” survival (including C9orf64, FAM96A, CDH1 and CDH17), respectively. STRING analysis of these proteins indicated a tight protein-protein interaction network centered on TP53. Ingenuity pathway analysis linked proteins representing “activated stroma factors” and “basal tumor factors” to poor prognosis of PDAC. It also highlighted TCF1 and CTNNB1 as possible upstream regulators. Further parallel reaction monitoring verified that seven proteins were upregulated in patients with “short” survival (MMP9, CLIC3, MMP8, PRTN3, P4HA2, THBS1 and FN1), while 18 proteins were upregulated in patients with “long” survival, including EPCAM, LGALS4, VIL1, CLCA1 and TPPP3. Thus, we verified 25 protein biomarker candidates for PDAC prognosis at the tissue level. Furthermore, an activated stroma status and protein-protein interactions with TP53 might be linked to poor prognosis of PDAC.

• biomarker
• pancreatic ductal adenocarcinoma
• proteome
• survival
• tumor microenvironment

• breast X-ray photography technique
• breast cancer
• cyclooxygenase-2
• proliferating cell nuclear antigen
• proliferation-associated nuclear antigen (Ki-67)

Cutaneous melanoma is a very deadly cancer because of its proclivity to metastasize. Despite the recent development of targeted and immune therapies, patient survival remains low. It is therefore crucial to enhance understanding of the molecular mechanisms underlying invasion. We previously identified tetraspanin 8 (TSPAN8) as an important modulator of melanoma invasiveness, and several of its transcriptional regulators, which affect TSPAN8 expression during melanoma progression toward an invasive stage. This study found that TSPAN8 promoter contains consensus-binding sites for p53 transcription factor. We demonstrated that p53 silencing was sufficient to turn on Tspan8 expression in non-invasive melanoma cells and that p53 acts as a direct transcriptional repressor of TSPAN8. We also showed that p53 modulated matrigel invasion in melanoma cells in a TSPAN8-dependent manner. In conclusion, this study reveals p53 as a negative regulator of Tspan8 expression. As TP53 gene is rarely mutated in melanoma, it was hitherto poorly studied but its role in apoptosis and growth suppression in melanoma is increasingly becoming clear. The study highlights the importance of p53 as a regulator of melanoma invasion and the concept that reactivating p53 could provide a strategy for modulating not only proliferative but also invasive capacity in melanoma treatment.

• cancer stem cell
• molecular markers
• systemic review

Epithelial cell adhesion molecule (EpCAM) is known to be overexpressed in epithelial cancers associated with enhanced malignant potential, particularly colorectal carcinoma (CRC) and head and neck squamous cell carcinoma (HNSCC). However, it is unknown whether progression of malignance can be directly inhibited by targeting EpCAM. Here, we have generated five novel monoclonal antibodies (mAbs) against EpCAM. One of these anti-EpCAM mAbs, EpAb2-6, was found to induce cancer cell apoptosis in vitro, inhibit tumor growth, and prolong the overall survival of both a pancreatic cancer metastatic mouse model and mice with human colon carcinoma xenografts. EpAb2-6 also increases the therapeutic efficacy of irinotecan, fluorouracil, and leucovorin (IFL) therapy in a colon cancer animal model and gemcitabine therapy in a pancreatic cancer animal model. Furthermore, EpAb2-6, which binds to positions Y95 and D96 of the EGF-II/TY domain of EpCAM, inhibits production of EpICD, thereby decreasing its translocation and subsequent signal activation. Collectively, our results indicate that the novel anti-EpCAM mAb can potentially be used for cancer-targeted therapy.

• EpCAM
• cancer therapy
• colorectal carcinoma
• targeting imaging
• therapeutic antibody

Pancreatic cancer (PaCa) has the highest death rate and incidence is increasing. Poor prognosis is due to late diagnosis and early metastatic spread, which is ascribed to a minor population of so called cancer stem cells (CSC) within the mass of the primary tumor. CSC are defined by biological features, which they share with adult stem cells like longevity, rare cell division, the capacity for self renewal, differentiation, drug resistance and the requirement for a niche. CSC can also be identified by sets of markers, which for pancreatic CSC (Pa-CSC) include CD44v6, c-Met, Tspan8, alpha6beta4, CXCR4, CD133, EpCAM and claudin7. The functional relevance of CSC markers is still disputed. We hypothesize that Pa-CSC markers play a decisive role in tumor progression. This is fostered by the location in glycolipid-enriched membrane domains, which function as signaling platform and support connectivity of the individual Pa-CSC markers. Outside-in signaling supports apoptosis resistance, stem cell gene expression and tumor suppressor gene repression as well as miRNA transcription and silencing. Pa-CSC markers also contribute to motility and invasiveness. By ligand binding host cells are triggered towards creating a milieu supporting Pa-CSC maintenance. Furthermore, CSC markers contribute to the generation, loading and delivery of exosomes, whereby CSC gain the capacity for a cell-cell contact independent crosstalk with the host and neighboring non-CSC. This allows Pa-CSC exosomes (TEX) to reprogram neighboring non-CSC towards epithelial mesenchymal transition and to stimulate host cells towards preparing a niche for metastasizing tumor cells. Finally, TEX communicate with the matrix to support tumor cell motility, invasion and homing. We will discuss the possibility that CSC markers are the initial trigger for these processes and what is the special contribution of CSC-TEX.

• Pancreatic cancer
• Cancer stem cells
• Stem cell markers
• Exosomes
• Crosstalk

• Adenocarcinoma/genetics
• Adenocarcinoma/metabolism
• Biomarkers, Tumor/genetics
• Biomarkers, Tumor/metabolism
• Epithelial-Mesenchymal Transition/genetics
• Exosomes/metabolism
• Gene Expression Regulation, Neoplastic
• Humans
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Neoplastic Stem Cells/metabolism
• Pancreatic Neoplasms/genetics
• Pancreatic Neoplasms/metabolism

• Liver stem cell
• biliary differentiation
• bipotency
• hepatic differentiation
• hepatoblast
• human liver development
• liver progenitor
• pluripotent stem cells

• claudin7 palmitoylation
• complex-dependent bioactivity
• glycolipid-enriched membrane microdomains
• metastasis

• Adenocarcinoma/genetics
• Adenocarcinoma/metabolism
• Adenocarcinoma/pathology
• Animals
• Cell Line, Tumor
• Cell Movement/genetics
• Claudins/genetics
• Claudins/metabolism
• Cytosol/metabolism
• Exosomes/metabolism
• Gene Knockdown Techniques
• Glycolipids/metabolism
• Lipoylation
• Membrane Microdomains/metabolism
• Membrane Proteins/metabolism
• Neoplasm Metastasis
• Pancreatic Neoplasms/genetics
• Pancreatic Neoplasms/metabolism
• Pancreatic Neoplasms/pathology
• Phosphatidylinositol 3-Kinases/metabolism
• Proto-Oncogene Proteins c-akt/metabolism
• Rats
• Signal Transduction
• Transcription Factors/metabolism

The low survival rate of hepatocellular carcinoma (HCC) is partly attributable to its resistance to existing chemotherapeutic agents. Until now, there have been limited chemotherapeutic agents for liver cancer. Epithelial cell adhesion molecule (EpCAM) has been found to be over-expressed during stages of carcinogenesis and has been associated with poor overall survival in many cancers. The aim of this study was to evaluate EpCAM expression in HCC and evaluate the effects of EpCAM to established chemotherapy.

Three human hepatocellular carcinoma cell lines—HepG2, Hep3B and HuH-7—were pre- and post-treated with doxorubicin, 5-fluorouracil (5-FU) and cisplatin. Cell viability and EpCAM protein expression were measured by MTT assay and Western Blotting respectively. EpCAM positive cells were analyzed by flow cytometry. To evaluate the effects of doxorubicin efficacy on EpCAM positive cells, a small interfering RNA (siRNA) specific to EpCAM was transfected into the cells and treated with doxorubicin. Results: EpCAM was significantly down-regulated by doxorubicin treatment in all three HCC cell lines (P <0.05 or 0.01). EpCAM expression was down-regulated by the 5-FU and cisplatin in HepG2 cells, however the EpCAM expression was up-regulated by 5-FU and cisplatin in Hep3B cell line. EpCAM expression was down-regulated by 5-FU, and up-regulated by cisplatin in Huh-7 cell line. Flow cytometry assay showed doxorubicin exposure decreased EpCAM positive cell quantities in three HCC cell lines. EpCAM siRNA knock-down attenuated cell mortality after doxorubicin exposure.

All of these findings demonstrate that EpCAM is one of targets of chemoresistence.

• 5-FU
• Cisplatin
• Doxorubicin
• Epithelial cell adhesion molecule
• Hepatocellular carcinoma

In colorectal cancer (CoCa) EpCAM is frequently associated with claudin-7. There is evidence that tumor-promoting EpCAM activities are modulated by the association with claudin-7. To support this hypothesis, claudin-7 was knocked-down (kd) in HT29 and SW948 cells.

HT29-cld7^kd and SW948-cld7^kd cells display decreased anchorage-independent growth and the capacity for holoclone-, respectively, sphere-formation is reduced. Tumor growth is delayed and cld7^kd cells poorly metastasize. In line with this, migratory and invasive potential of cld7^kd clones is strongly impaired, migration being inhibited by anti-CD49c, but not anti-EpCAM, although motility is reduced in EpCAM siRNA-treated cells. This is due to claudin-7 recruiting EpCAM in glycolipid-enriched membrane fractions towards claudin-7-associated TACE and presenilin2, which cleave EpCAM. The cleaved intracellular domain, EpIC, promotes epithelial-mesenchymal transition (EMT)-associated transcription factor expression, which together with fibronectin and vimentin are reduced in claudin-7^kd cells. But, uptake of HT29^wt and SW948^wt exosomes by the claudin-7^kd lines sufficed for transcription factor upregulation and for restoring motility.

Thus, claudin-7 contributes to motility and invasion and is required for recruiting EpCAM towards TACE/presenilin2. EpIC generation further supports motility by promoting a shift towards EMT. Notably, EMT features of cld7-competent metastatic CoCa cells can be transferred via exosomes to poorly metastatic cells.

• ADAM
• cell adhesion
• epithelial cell adhesion molecule (EPCAM)
• proteolysis
• β-secretase 1 (BACE1)

• EpCAM
• hepatic stem/progenitor cell
• liver differentiation
• liver regeneration
• signaling

Identification of key drivers and new therapeutic targets is important given the poor prognosis for hepatocellular carcinoma (HCC) patients, particularly those ineligible for surgical resection or liver transplant. However, the approach to identify such driver genes is facing significant challenges due to the genomically heterogenous nature of HCC. Here, we tested whether the integrative genomic profiling of a well-defined HCC subset that is classified by an extreme EpCAM⁺ AFP⁺ gene expression signature and associated with poor prognosis, all attributes of a stem cell-like phenotype, could uncover survival-related driver genes in HCC. Following transcriptomic analysis of the well-defined HCC cases, a Gene Set Enrichment Analysis (GSEA) coupled with genomic copy number alteration assessment revealed that YY1-associated protein 1 (YY1AP1) is a critical oncoprotein specifically activated in EpCAM⁺ AFP⁺ HCC. YY1AP1 silencing eliminates oncogene addiction by altering the chromatin landscape and triggering massive apoptosis in vitro and tumor suppression in vivo. YY1AP1 expression promotes HCC proliferation and is required for the maintenance of stem cell features. We revealed that YY1AP1 cooperates with YY1 to alter the chromatin landscape and activate transcription of stemness regulators. Thus, YY1AP1 may serve as a key molecular target for EpCAM⁺ AFP⁺ HCC subtype. Our results demonstrate the feasibility and power of a new strategy by utilizing well-defined patient samples and integrative genomics to uncover critical pathways linked to HCC subtypes with prognostic impact.

• Cell migration
• EGF
• EpCAM
• Ovarian cancer

• Antigens, Neoplasm/genetics
• Antigens, Neoplasm/metabolism
• Cell Adhesion Molecules/antagonists & inhibitors
• Cell Adhesion Molecules/genetics
• Cell Adhesion Molecules/metabolism
• Cell Line, Tumor
• Cell Movement/genetics
• Cell Movement/physiology
• Epidermal Growth Factor/metabolism
• Epithelial Cell Adhesion Molecule
• ErbB Receptors/antagonists & inhibitors
• ErbB Receptors/genetics
• Female
• Gene Knockdown Techniques
• Humans
• MAP Kinase Signaling System
• Ovarian Neoplasms/genetics
• Ovarian Neoplasms/metabolism
• Ovarian Neoplasms/physiopathology
• RNA, Messenger/genetics
• RNA, Messenger/metabolism
• RNA, Neoplasm/genetics
• RNA, Neoplasm/metabolism
• RNA, Small Interfering/genetics
• Up-Regulation

• Canadian Institutes of Health Research

• epcam
• ctcs
• dtcs
• emt
• met
• metastases

• Antigens, Neoplasm/metabolism
• Cell Adhesion Molecules/metabolism
• Disease Progression
• Epithelial Cell Adhesion Molecule
• Epithelial-Mesenchymal Transition
• Gene Expression Regulation, Neoplastic
• Humans
• Neoplasm Metastasis
• Neoplasms/metabolism
• Neoplasms/pathology
• Neoplasms/physiopathology
• Neoplastic Cells, Circulating/metabolism

Regulated intramembrane proteolysis of Epithelial cell adhesion molecule (EpCAM) results in release of its intracellular domain (Ep-ICD) which triggers oncogenic signalling. The clinical significance of Ep-ICD in breast cancer remains to be determined. Herein, we examined the expression of nuclear and cytoplasmic Ep-ICD, and membranous extracellular domain of EpCAM (EpEx) in breast cancer patients, to determine its potential utility in predicting aggressive clinical course of the disease.

In this retrospective study, 266 breast cancers and 45 normal breast tissues were immunohistochemically analyzed to determine the expression patterns of nuclear and cytoplasmic Ep-ICD and membranous EpEx and correlated with clinicopathological parameters and follow up. Disease-free survival was determined by Kaplan-Meier method and multivariate Cox regression analysis.

Nuclear Ep-ICD was more frequently expressed in breast cancers compared to normal tissues. Significant association was observed between increased nuclear Ep-ICD expression and reduced disease-free survival in patients with ductal carcinoma in situ (DCIS) and invasive ductal carcinoma (IDC) (p < 0.001). Nuclear Ep-ICD was positive in all the 13 DCIS and 25 IDC patients who had reduced disease-free survival, while none of the nuclear Ep-ICD negative DCIS or IDC patients had recurrence during the follow up period. Notably, majority of IDC patients who had recurrence had early stage tumors. Multivariate Cox regression analysis identified nuclear Ep-ICD as the most significant predictive factor for reduced disease-free survival in IDC patients (p = 0.011, Hazard ratio = 80.18).

Patients with nuclear Ep-ICD positive breast cancers had poor prognosis. The high recurrence of disease in nuclear Ep-ICD positive patients, especially those with early tumor stage suggests that nuclear Ep-ICD accumulation holds the promise of identifying early stage patients with aggressive disease who are likely to be in need of more rigorous post-operative surveillance and/or treatment.

• Adenocarcinoma, Mucinous/diagnosis
• Adenocarcinoma, Mucinous/metabolism
• Adenocarcinoma, Mucinous/mortality
• Aged
• Antigens, Neoplasm/metabolism
• Cell Adhesion Molecules/metabolism
• Cohort Studies
• Cystadenocarcinoma, Serous/diagnosis
• Cystadenocarcinoma, Serous/metabolism
• Cystadenocarcinoma, Serous/mortality
• Epithelial Cell Adhesion Molecule
• Female
• Humans
• Middle Aged
• Ovarian Neoplasms/diagnosis
• Ovarian Neoplasms/metabolism
• Ovarian Neoplasms/mortality
• Prognosis
• Survival Analysis
• Up-Regulation

• Antineoplastic Agents/toxicity
• Apoptosis/drug effects
• Carbazoles/pharmacology
• Carcinoma/drug therapy
• Carcinoma/genetics
• Carcinoma/metabolism
• Carcinoma/physiopathology
• Cell Line, Tumor
• Colonic Neoplasms/drug therapy
• Colonic Neoplasms/genetics
• Colonic Neoplasms/metabolism
• Colonic Neoplasms/physiopathology
• DNA-Binding Proteins/genetics
• DNA-Binding Proteins/metabolism
• Drug Combinations
• Drug Synergism
• Fluorouracil/toxicity
• Humans
• Murraya/chemistry
• Nuclear Proteins/genetics
• Nuclear Proteins/metabolism
• PTEN Phosphohydrolase/genetics
• PTEN Phosphohydrolase/metabolism
• Plant Extracts/pharmacology
• Reactive Oxygen Species/metabolism
• Rutaceae/chemistry
• Tumor Protein p73
• Tumor Suppressor Protein p53/genetics
• Tumor Suppressor Protein p53/metabolism
• Tumor Suppressor Proteins/genetics
• Tumor Suppressor Proteins/metabolism

• CDE, cell cycle-dependent element
• CDKN1A
• CHR, cell cycle genes homology region
• ChIP, chromatin immunoprecipitation
• DREAM complex
• DREAM, DP, RB-like, E2F4, and MuvB complex
• E2F/RB complex
• HPV, human papilloma virus
• NF-Y, Nuclear factor Y
• cdk, cyclin-dependent kinase
• genome-wide meta-analysis
• p53

• Binding Sites
• Chromatin Immunoprecipitation
• Cyclin-Dependent Kinase Inhibitor p21/genetics
• Cyclin-Dependent Kinase Inhibitor p21/metabolism
• E2F Transcription Factors/chemistry
• E2F Transcription Factors/genetics
• E2F Transcription Factors/metabolism
• HCT116 Cells
• Humans
• Meta-Analysis as Topic
• Promoter Regions, Genetic
• Protein Binding
• RNA, Messenger/metabolism
• RNA, Untranslated/metabolism
• Real-Time Polymerase Chain Reaction
• Repressor Proteins/genetics
• Repressor Proteins/metabolism
• Retinoblastoma Protein/genetics
• Retinoblastoma Protein/metabolism
• Signal Transduction
• Transcriptional Activation
• Tumor Suppressor Protein p53/chemistry
• Tumor Suppressor Protein p53/genetics
• Tumor Suppressor Protein p53/metabolism

The Epithelial Cell Adhesion Molecule (EpCAM) has been shown to be strongly expressed in human breast cancer and cancer stem cells and its overexpression has been supposed to support tumor progression and metastasis. However, effects of EpCAM overexpression on normal breast epithelial cells have never been studied before. Therefore, we analyzed effects of transient adenoviral overexpression of EpCAM on proliferation, migration and differentiation of primary human mammary epithelial cells (HMECs).

HMECs were transfected by an adenoviral system for transient overexpression of EpCAM. Thereafter, changes in cell proliferation and migration were studied using a real time measurement system. Target gene expression was evaluated by transcriptome analysis in proliferating and polarized HMEC cultures. A Chicken Chorioallantoic Membrane (CAM) xenograft model was used to study effects on in vivo growth of HMECs.

EpCAM overexpression in HMECs did not significantly alter gene expression profile of proliferating or growth arrested cells. Proliferating HMECs displayed predominantly glycosylated EpCAM isoforms and were inhibited in cell proliferation and migration by upregulation of p27^KIP1 and p53. HMECs with overexpression of EpCAM showed a down regulation of E-cadherin. Moreover, cells were more resistant to TGF-β1 induced growth arrest and maintained longer capacities to proliferate in vitro. EpCAM overexpressing HMECs xenografts in chicken embryos showed hyperplastic growth, lack of lumen formation and increased infiltrates of the chicken leukocytes.

EpCAM revealed oncogenic features in normal human breast cells by inducing resistance to TGF-β1-mediated growth arrest and supporting a cell phenotype with longer proliferative capacities in vitro. EpCAM overexpression resulted in hyperplastic growth in vivo. Thus, we suggest that EpCAM acts as a prosurvival factor counteracting terminal differentiation processes in normal mammary glands.

• Animals
• Antigens, Neoplasm/metabolism
• Cell Adhesion Molecules/metabolism
• Cell Communication
• Cell Membrane/metabolism
• Cell Membrane/pathology
• Epithelial Cell Adhesion Molecule
• Humans
• Mice
• Neoplasms/metabolism
• Neoplasms/pathology

Epithelial cell adhesion molecule (EpCAM) is frequently expressed in breast cancer, and its expression has been associated with poor prognosis. Breast cancer can be subdivided into intrinsic subtypes, differing in prognosis and response to therapy.

To investigate the association between EpCAM expression and prognosis in the intrinsic subtypes of breast cancer, we performed immunohistochemical studies on a tissue microarray encompassing a total of 1365 breast cancers with detailed clinicopathological annotation and outcomes data.

We observed EpCAM expression in 660 out of 1365 (48%) cases. EpCAM expression varied significantly in the different intrinsic subtypes. In univariate analyses of all cases, EpCAM expression was associated with a significantly worse overall survival. In the intrinsic subtypes, EpCAM expression was associated with an unfavourable prognosis in the basal-like and luminal B HER2⁺ subtypes but associated with a favourable prognosis in the HER2 subtype. Consistently, specific ablation of EpCAM resulted in increased cell viability in the breast cancer cell line SKBR3 (ER⁻, PR⁻, and HER2⁺) but decreased viability in the breast cancer cell line MDA-MB-231 (ER⁻, PR⁻, and HER2⁻ ).

The differential association of EpCAM expression with prognosis in intrinsic subtypes has important implications for the development of EpCAM-targeted therapies in breast cancer.