1: Breast Cancer Res Treat. 2006 Nov;100(2):139-48. Epub 2006 Jun 22.


E-cadherin immunohistochemical expression as a prognostic factor in infiltrating ductal carcinoma of the breast: a systematic review and meta-analysis.

Gould Rothberg BE, Bracken MB.

Section of Chronic Disease Epidemiology, Yale University School of Public Health, 60 College Street, PO Box 208034, New Haven, CT 06520-8034, USA. bonnie.gouldrothberg@yale.edu

PURPOSE: Multiple studies examining the relationship between loss of E-cadherin expression, a pivotal event for evolving metastatic behavior among epithelially derived cancers, and 5-year survival in infiltrating ductal breast carcinoma have yielded inconclusive and contradictory results. EXPERIMENTAL DESIGN: We conducted a systematic review of the PubMed database through August 2005 with no language restrictions to identify cohort studies that evaluated E-cadherin immunohistochemical expression as a prognostic marker for ductal breast carcinoma. 5-year all-cause mortality or 5-year breast cancer-specific mortality were the primary study outcomes. Meta-analysis was conducted using the REVMAN software and summary hazard ratios assuming both fixed effect and random effect models were calculated. RESULTS: Ten retrospective cohort studies were identified. Reduced or absent E-cadherin expression significantly increased the risk of all-cause mortality [combined HR = 1.55; 95% CI = 1.08-2.23] whereas a non-significant association was observed for breast cancer-specific mortality [combined HR = 0.70; 95% CI = 0.39-1.27]. We documented substantial inter-study heterogeneity with respect to all aspects of clinical data collection, immunohistochemical staining and interpretation as well as statistical modeling. These factors could not be formally analyzed but they challenge the robustness of our calculated summary estimates. CONCLUSIONS: Loss of E-cadherin expression may be an independent negative prognostic indicator for infiltrating ductal breast carcinoma and randomized, controlled studies evaluating this finding are justified. We encourage standardization of immunohistochemical techniques, data interpretation algorithms across laboratories and use of all-cause mortality to increase data compatibility and facilitate future efforts summarizing the utility of alternate prognostic markers in cancer.

Publication Types:
Meta-Analysis
Review

PMID: 16791476 [PubMed - indexed for MEDLINE]

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2: J Exp Clin Cancer Res. 2006 Mar;25(1):5-14.


Role and expression patterns of E-cadherin in head and neck squamous cell carcinoma (HNSCC).

Georgolios A, Batistatou A, Manolopoulos L, Charalabopoulos K.

Department of Physiology, Clinical Unit, Medical Faculty, University of Ioannina, Ioannina, Greece.

E- cadherin is a member of the cadherin superfamily known as the main mediator of the cell- cell calcium dependent adhesion interactions. Research evidence also yields to this adhesion molecule an important role in carcinogenesis and tumor progression. This review focuses on the differential expression of E- cadherin in the various anatomic sites of the human body where HNSCC arises. Controversies in the results of various studies are discussed and possible prospects for application of all this developing knowledge to prognosis and therapy of the disease are briefly mentioned.

Publication Types:
Review

PMID: 16761612 [PubMed - indexed for MEDLINE]

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3: Inflammopharmacology. 2005;13(1-3):91-101.


Polyamines regulate expression of E-cadherin and play an important role in control of intestinal epithelial barrier function.

Wang JY.

Surgical Service, Baltimore Veterans Affairs Medical Center, 10 North Greene Street, Baltimore, MD 21201, USA. jwang@smail.umaryland.edu

Epithelial cells line the gastrointestinal mucosa and form an important barrier that protects the subepithelial tissue against a wide array of noxious substances, allergens, viruses and luminal microbial pathogens. Restoration of mucosal integrity following injury and various environmental stresses requires epithelial cell decisions that regulate signaling networks controlling gene expression, survival, migration and proliferation. Recently, it has been shown that polyamines play an important role in the regulation of cell-cell interactions and are critical for maintenance of intestinal epithelial integrity. Both the function of polyamines in expression of adherens junction proteins and their possible mechanisms, especially in implication of intracellular Ca2+ and c-Myc transcription factor, are the subject of this review article.

Publication Types:
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Review

PMID: 16259731 [PubMed - indexed for MEDLINE]

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4: Nippon Rinsho. 2004 Oct;62 Suppl 10:463-6.


[Mechanism of ovarian cancer metastasis--changes in E-cadherin expression]

[Article in Japanese]

Horiuchi A, Konishi I.

Department of Obstetrics and Gynecology, Shinshu University School of Medicine.

Publication Types:
Review

PMID: 15535288 [PubMed - indexed for MEDLINE]

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5: Biochim Biophys Acta. 2004 Apr 1;1691(1):1-15.


Regulation of E-cadherin expression and beta-catenin/Tcf transcriptional activity by the integrin-linked kinase.

Oloumi A, McPhee T, Dedhar S.

British Columbia Cancer Agency and Jack Bell Research Centre, University of British Columbia, Vancouver Hospital, 2660 Oak St. Vancouver, BC, Canada V6H 3Z6.

Integrin-linked kinase (ILK) is a serine/threonine protein kinase which interacts with the cytoplasmic domains of beta1 and beta3 integrins. ILK structure and its localization at the focal adhesion allows it not only to interact with different structural proteins, but also to mediate many different signalling pathways. Extracellular matrices (ECM) and growth factors each stimulate ILK signalling. Constitutive activation of ILK in epithelial cells results in oncogenic phenotypes such as disruption of cell extracellular matrix and cell to cell interactions, suppression of suspension-induced apoptosis, and induction of anchorage independent cell growth and cell cycle progression. More specifically, pathological overexpression of ILK results in down-regulation of E-cadherin expression, and nuclear accumulation of beta-catenin, leading to the subsequent activation of the beta-catenin/Tcf transcription complex, the downstream components of the Wnt signalling pathway. Here we review the data implicating ILK in the regulation of these two signalling pathways, and discuss recent novel insights into the molecular basis and requirement of ILK in the process of epithelial to mesenchymal transformation (EMT).

Publication Types:
Research Support, Non-U.S. Gov't
Review

PMID: 15053919 [PubMed - indexed for MEDLINE]

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6: Cancer Cell. 2003 Apr;3(4):307-10.


Connecting estrogen receptor function, transcriptional repression, and E-cadherin expression in breast cancer.

Fearon ER.

Division of Molecular Medicine and Genetics and the Cancer Center, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA. fearon@umich.edu

A recent paper in Cell (Fujita et al., 2003) demonstrates that MTA3, a novel component of the Mi-2/NuRD transcriptional repression complex, is an estrogen receptor-regulated inhibitor of the Snail zinc finger transcription factor in breast cancer. Given the important role of Snail in repressing E-cadherin transcription and the function of E-cadherin as a tumor suppressor protein and regulator of epithelial architecture, the findings offer potentially significant new insights into cancer pathogenesis.

Publication Types:
Review

PMID: 12726856 [PubMed - indexed for MEDLINE]

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7: Ophthalmologica. 2003 Jan-Feb;217(1):68-75.


Biomolecular markers of malignancy in human uveal melanoma: the role of the cadherin-catenin complex and gene expression profiling.

Conway RM, Cursiefen C, Behrens J, Naumann GO, Holbach LM.

Ocular Oncology Unit, Save Sight Institute, University of Sydney, Australia. max@eye.usyd.edu.au

In recent years there has been a trend towards conservative management of uveal melanoma (UM), aimed at preserving the eye and vision. Despite improvements with this approach, recurrent tumour and metastatic disease still occur, and the management remains problematic. As a result of these limitations, there is interest in gaining a greater understanding of molecular changes associated with aggressive disease patterns in UM. This might result in new, more effective and less toxic therapies as well as provide prognostic information for defining subgroups of patients with a less favourable prognosis as potential candidates for adjuvant therapies. Accumulating evidence over the past decade suggests that disturbance in the cadherin-catenin adhesion complex is critical in the process leading to invasion and metastasis of many cancers. The recent advent of DNA micro-array technology now offers an unprecedented ability to study these molecules and others associated with malignant transformation. In this mini-review, the aspects of tumour progression in which cadherin-catenin may be involved are dealt with along with the potential application of DNA micro-array technology to the problem in UM. Copyright 2003 S. Karger AG, Basel

Publication Types:
Review

PMID: 12566877 [PubMed - indexed for MEDLINE]

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8: Bull Soc Belge Ophtalmol. 2000;(278):55-9.


Cadherin expression in the eye.

Van Aken E, Papeleu P, De Potter P, De Laey JJ, Mareel M.

Dpt. Of Ophthalmology, Ghent University Hospital, Belgium.

E(pithelial)-cadherin and N(eural)-cadherin are transmembrane cell-cell adhesion molecules, belonging to the subfamily of classical cadherins. The expression of E- and N-cadherin is spatiotemporally regulated and associated with a variety of normal morphogenetic events. The expression of E- and N- cadherin is also involved in carcinogenesis. E-cadherin functions as a tumor-suppressor. N-cadherin, however, is associated with cancer progression. The study of the expression pattern of E- and N-cadherin in the normal and tumorous eye is the aim of our research.

Publication Types:
Research Support, Non-U.S. Gov't
Review

PMID: 11761562 [PubMed - indexed for MEDLINE]

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9: J Pathol. 2000 Apr;190(5):526-30.


Aberrant P-cadherin expression is a feature of clonal expansion in the gastrointestinal tract associated with repair and neoplasia.

Sanders DS, Perry I, Hardy R, Jankowski J.

Deptartment of Histopathology, The Medical School, Edgbaston, Birmingham, UK. d.s.a.sanders@bham.ac.uk

The recognition of key roles for cadherins in the determination of epithelial cell phenotype, migration, differentiation, and tumour dissemination have stimulated much interest in this family of adhesion molecules. In the gastrointestinal tract, alteration of the expression of classical cadherins with aberrant P-cadherin up-regulation, associated with co-expression or loss of E-cadherin expression, is seen in neoplastic transformation of oral and oesophageal squamous mucosa and in lesions representing early neoplastic transformation of glandular mucosa, such as aberrant crypt foci and metaplastic and adenomatous polyps. This same phenotype is seen in enterocytes adjacent to foci of ulceration in the intestine in colitis, including inflammatory bowel disease, and in colitis-associated dysplasia. In coeliac disease, reversible E-cadherin down-regulation correlates with the degree of villous atrophy, but in contrast with colitis, aberrant P-cadherin expression is not a feature. Aberrant epithelial P-cadherin expression is thus associated with a proliferative phenotype related to ulceration and neoplastic transformation in the gastrointestinal tract, which may confer a survival advantage on these cells, but the relative functional roles of P-cadherin and E-cadherin and the molecular mechanisms underlyingP-cadherin/catenin interactions have yet to be elucidated. Copyright 2000 John Wiley & Sons, Ltd.

Publication Types:
Review

PMID: 10727977 [PubMed - indexed for MEDLINE]

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10: Microsc Res Tech. 1998 Nov 1;43(3):218-23.


Distinct P-cadherin expression in cultured normal human keratinocytes and squamous cell carcinoma cell lines.

Wakita H, Shirahama S, Furukawa F.

Department of Dermatology, Hamamatsu University School of Medicine, Japan. wakita@hama-med.ac.jp

Spatially regulated expression of E (epithelial)- and P (placental)-cadherins is crucial for maintaining normal epidermal architecture. In cutaneous squamous cell carcinomas (SCCs), aberrant P-cadherin expression is often observed in "squamoid" cancer cells, whereas E-cadherin expression in cancer cells is generally reduced. Therefore, it is plausible that SCC cells have acquired the ability to express P-cadherin and that P-cadherin plays a role in tumor progression. To address the issue, the in vitro effect of extracellular calcium on differentiation is a good model for investigating P-cadherin in normal and neoplastic skin. With elevations in extracellular calcium, human SCC cell line (DJM-1) cells initiate de novo synthesis of P-cadherin and express P-cadherin on the cell surface, whereas in normal human keratinocytes, P-cadherin expression on the cell surface is enhanced via the translocation from the cytosol to the cell membrane and/or the stabilization of P-cadherin at the cell surface. DJM-1 cells maintain P-cadherin expression on the cell surface at high levels for over 4 days after calcium elevation, whereas normal human keratinocytes cannot sustain cell surface P-cadherin when the cells are cultured in high calcium for more than 2 days. P-cadherin synthesis in DJM-1 cells is regulated at translational levels by extracellular calcium concentrations. SCC cells have the ability to produce P-cadherin by a mechanism not observed in normal keratinocytes, which might relate to the aberrant expression of P-cadherin in SCC of the skin.

Publication Types:
Research Support, Non-U.S. Gov't
Review

PMID: 9840799 [PubMed - indexed for MEDLINE]

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11: Exp Cell Res. 1995 Oct;220(2):243-56.


Cadherin expression in the developing vertebrate CNS: from neuromeres to brain nuclei and neural circuits.

Redies C.

Department of Biochemistry, Max-Planck-Institute for Developmental Biology, Tübingen, Germany.

Cadherins are a family of cell surface glycoproteins which mediate cell-cell adhesion by a Ca(2+)-dependent mechanism. Results from in vitro studies with cadherin-transfected cell lines show that cadherins preferentially bind to each other in a homophilic fashion. In the developing vertebrate brain, at least 10 cadherins are found. Some of these cadherins are expressed in a restricted fashion in particular developing brain nuclei and neural circuits. Based on these results, specific morphogenetic roles for cadherins during CNS development have been proposed. This review focuses on the possible role of cadherin-mediated sorting and aggregation of early neurons and neurites in the formation of brain nuclei, fiber tracts, and neural circuits. Moreover, at least 1 cadherin is also expressed in a segmental ("neuromeric") fashion in the early chicken forebrain, suggesting that this cadherin regulates developmental processes involved in the transformation from the neuromeric organization of the early neuroepithelium to the functional organization of the mature brain.

Publication Types:
Research Support, Non-U.S. Gov't
Review

PMID: 7556431 [PubMed - indexed for MEDLINE]

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12: Biochim Biophys Acta. 1994 May 27;1198(1):11-26.


Cadherin expression in carcinomas: role in the formation of cell junctions and the prevention of invasiveness.

Birchmeier W, Behrens J.

Max-Delbrück-Centrum, Berlin, Germany.

It has been realized that the loss of epithelial differentiation in carcinomas, which is accompanied by higher mobility and invasiveness of the tumor cells, is often a consequence of reduced intercellular adhesion. A variety of recent reports have indicated that the primary cause for the 'scattering' of the cells in invasive carcinomas is a disturbance of the integrity of intercellular junctions, often involving loss of a functional cell-cell adhesion molecule E-cadherin. It has also been suggested that during invasion, carcinoma cells convert to a sort of mesenchymal stage, as do normal epithelial cells during development. In the present review, permanent and transient molecular mechanisms are discussed which lead to the impairment of junction integrity of the epithelial cells and thus to the progression of carcinomas towards a more metastatic state. Furthermore, the now extensive literature on the down-regulation of E-cadherin expression in human and animal carcinomas is reviewed in detail.

Publication Types:
Research Support, Non-U.S. Gov't
Review

PMID: 8199193 [PubMed - indexed for MEDLINE]

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13: Int J Dev Biol. 1993 Mar;37(1):227-35.


Erratum in:
Int J Dev Biol 1993 Dec;37(4):following 8.

Expression of E-cadherin in embryogenetic ingression and cancer invasion.

Mareel M, Bracke M, Van Roy F, Vakaet L.

Department of Radiotherapy and Nuclear Medicine, University Hospital, Ghent, Belgium.

Homophilic interactions of E-cadherin serve the organization of embryonic and adult epithelia and counteract cancer invasion. The role of E-cadherin as an invasion-suppressor molecule has been demonstrated cancer. Regulation of embryonic ingression and cancer invasion via E-cadherin occurs at transcriptional, translational and post-translation levels.

Publication Types:
Research Support, Non-U.S. Gov't
Review

PMID: 8507565 [PubMed - indexed for MEDLINE]

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14: Cancer Metastasis Rev. 1993 Mar;12(1):29-37.


Decreased expression of the intercellular adhesion molecule E-cadherin in prostate cancer: biological significance and clinical implications.

Giroldi LA, Schalken JA.

Urological Research Laboratory, University Hospital Nijmegen, The Netherlands.

Publication Types:
Review

PMID: 8448824 [PubMed - indexed for MEDLINE]

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15: Bull Cancer. 1992;79(4):347-55.


E-cadherin expression: a counterbalance for cancer cell invasion.

Mareel M, Vleminckx K, Vermeulen S, Bracke M, Van Roy F.

Department of Radiotherapy and Nuclear Medicine, University of Ghent, Belgium.

Invasion, eventually leading to metastasis, is presented as the result of a balance between the activation of 2 sets of genes, coined i+ (invasion promotor) and i- (invasion suppressor) genes. Experiments in vitro have indicated that the homotypic homophilic epithelial cell--cell adhesion molecule E-cadherin (L-CAM; uvomorulin; cell CAM 120/80; Arc-1; rrl antigen) is an i- gene product. In several cell families, manipulation of E-cadherin at the level of the protein by antibody-mediated inactivation, at the level of the mRNA by antisense DNA transfection, and at the level of the genome by sense DNA transfection respectively resulted in induction and suppression of invasiveness. Nude mouse tumors from non-invasive homogeneously E-cadherin-positive cell populations were found to be invasive and metastatic. These tumors expressed E-cadherin in a heterogeneous manner, the undifferentiated cells being negative; but tumor-derived cells in culture were again E-cadherin-positive, indicating downregulation of this protein by host factors. Several types of human cancers showed a similar heterogeneity suggesting a relationship between downregulation of E-cadherin and invasion. Our current research focus is on the factors responsible for E-cadherin downregulation in experimental and human cancers.

Publication Types:
Research Support, Non-U.S. Gov't
Review

PMID: 1421692 [PubMed - indexed for MEDLINE]