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CDH1

MIM.192090 16q22.1 E-cadherin

Thursday 20 December 2007

E-cadherin, cadherin-1, uvomorulin, epithelial cadherin

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Definition: Cadherin-1 (cadherin-E) is a specific calcium ion-dependent cell adhesion molecule. E-cadherin is simultaneously a major cell-adhesion molecule, a tumour suppressor protein, a determinant of cell polarity and a partner to the potent catenin signalling molecules.

Functions

E-cadherins mediate homotypic adhesions in epithelial tissue, thus serving to keep the epithelial cells together and to relay signals between the cells. In several epithelial tumors, including adenocarcinomas of the colon and breast, there is a down-regulation of E-cadherin expression. Presumably, this down-regulation reduces the ability of cells to adhere to each other and facilitates their detachment from the primary tumor and their advance into the surrounding tissues.

E-cadherins are linked to the cytoskeleton by the catenins, proteins that lie under the plasma membrane. The normal function of E-cadherin is dependent on its linkage to catenins. In some tumors, E-cadherin is normal, but its expression is reduced because of mutations in the gene for a catenin.

During E-cadherin intracellular trafficking, E-cadherin is trafficked to and from the cell surface by exocytic and multiple endocytic pathways. A complex vesicle-trafficking machinery is responsible for the sorting, transport, actin association and vesicle targeting of E-cadherin to regulate its movement and function during growth and development and, possibly, in cancer.

- cell-cell adhesion

Epithelial-cadherin molecules (CDH1) that are expressed on the plasma membranes of adjacent cells probably interact in a zipper-like fashion. The most amino-terminal cadherin (CAD) domain on each E-cadherin molecule contains the histidine-alanine-valine (HAV) motif that is thought to interact with E-cadherin molecules of adjacent cells.

Cadherin molecules interact through their tips in cis and in trans in a highly flexible manner. The cytoplasmic cell-adhesion complex (CCC), consisting of -catenin, -catenin, -catenin (plakoglobin) and p120-catenin, links E-cadherin homodimers to the actin cytoskeleton.

Neural cell-adhesion molecule (NCAM), a member of the immunoglobulin (Ig)-like CAM superfamily, interacts through its first two Ig-like domains in a homophilic manner with NCAM molecules on neighbouring cells.

Different NCAM isoforms exist, which are either linked to the plasma membrane by a glycosylphosphatidylinositol (GPI) anchor (NCAM120) or have transmembrane and cytoplasmic domains (NCAM140 and NCAM180).

NCAM140 can associate through its cytoplasmic domain with the SRC family kinase FYN. NCAM also interacts with components of the extracellular matrix (ECM). The various isoforms of NCAM are differentially polysialylated, a post-translational modification that modulates their adhesive functions.

Pathology

- constitutional mutations in autosomal dominant familial gastric cancer (MIM.137215) (CDH1-associated gastric adenocarcinoma)

- constitutional mutations in susceptibility to Listeria monocytogenes

- reduced expression of E-cadherin in cancer invasion and metastasis trigger. E-cadherin-mediated cell-cell adhesion is lost during the development of most epithelial cancers.

  • low E-cadherin expression in plasmacytoid, signet ring cell and micropapillary variants of urothelial carcinoma (20818341)

- somatic mutations in several carcinomas

Loss of E-cadherin in tumorigenesis

Most human cancers originate from epithelial tissue. E-cadherin (CDH1) is the prototype member of the classical cadherin family. CDH1 is the key player in inducing cell polarity and organizing an epithelium. In most cancers of epithelial origin, E-cadherin-mediated cell-cell adhesion is lost concomitantly with progression towards tumour malignancy. Although E-cadherin expression can still be found in differentiated tumours in patients, there is an inverse correlation between E-cadherin levels, tumour grade and patient mortality rates.

Loss of cadherin-E expression can favor the malignant phenotype by allowing easy disaggregation of cells, which can then invade locally or metastasize. Reduced cell-surface expression of E-cadherin has been noted in many types of cancers, including those that arise in the esophagus, colon, breast, ovary, and prostate. The molecular basis of reduced E-cadherin expression is varied. In a small proportion of cases, there are mutations in the E-cadherin gene (located on 16q); in other cancers, E-cadherin expression is reduced as a secondary effect of mutations in β-catenin genes.

The loss of E-cadherin function during tumour progression can be caused by various genetic or epigenetic mechanisms.

- CDH1 mutations

In patients with diffuse gastric cancer and lobular breast cancer, and at a lower incidence in thyroid, bladder and gynaecological cancers, the E-cadherin gene is mutated, leading to the expression of a non-functional protein. Such mutations have also been found in families that are predisposed to the development of diffuse gastric cancer.

- downregulation of CDH1 expression

E-cadherin expression can be downregulated at the transcriptional level. The zinc-finger-containing proteins Snail, Slug and SIP1, and the helix-loop-helix transcription factor E12/E47 are important transcriptional repressors that bind to E2 boxes in the promoter of the E-cadherin gene and actively repress its expression.

Interestingly, MTA3, a recently identified component of the Mi-2/NuRD transcriptional co-represssor complex, links Snail expression to oestrogen-receptor (ER) activity: ER signalling upregulates MTA3 to repress Snail expression.

In turn, the lack of Snail allows unimpeded E-cadherin expression, so preventing tumour invasion. This connection might be one of the several mechanisms linking positive ER status with good prognosis in patients with breast cancer.

As a direct consequence of transcriptional inactivation, the E-cadherin gene locus is epigenetically silenced by hypermethylation, leading to further downregulation of E-cadherin expression. For example, the E-cadherin promoter is hypermethylated in 83% of thyroid carcinomas and at comparably high levels in many other cancer types.

Proteolytic degradation of E-cadherin by matrix metalloproteases (MMPs)

Proteolytic degradation of E-cadherin by matrix metalloproteases (MMPs) is another mechanism by which E-cadherin-mediated cell-cell adhesion can be ablated.

A soluble 80-kDa form of E-cadherin, produced by the degradation of the full-length protein, is frequently found in cultured tumour cell lines and in tumour biopsy samples.

This soluble form of E-cadherin promotes tumour-cell invasion by upregulating MMPs, such as MMP2, MMP9 and MMP. Such ectodomain shedding of E-cadherin might have an active part in the invasive process during tumour progression.

A novel transmembrane protein, dysadherin, interferes with E-cadherin function by downregulating its protein levels, without affecting messenger RNA levels, and it induces the metastatic spread of tumour cells in xenograft transplantation experiments.

- tyrosine phosphorylation

Tyrosine phosphorylation has been previously implicated in the regulation of cadherin function: receptor tyrosine kinases (RTKs), which are frequently activated in cancer cells), such as epidermal growth factor receptor (EGFR), hepatocyte growth factor receptor (MET) and fibroblast growth-factor receptor (FGFR), and the non-RTK SRC, phosphorylate E-cadherin, neuronal (N)-cadherin, beta-catenin (CTTN1), gamma-catenin (JUP) and p120-catenin (CTNND1), resulting in the disassembly of the CCC and, with it, the disruption of cadherin-mediated cell-cell adhesion.

- CDH1 mutations

Mutations in the E-cadherin gene are associated with diffuse-type gastric cancer and lobular breast carcinomas, and down-regulation of E-cadherin expression has been described in many types of cancer.

- CDH1 down-regulation

Loss or absence of E-cadherin is associated with aggressive histopathological characteristics such as tumor invasiveness and metastasis. In primary colorectal tumors, loss of E-cadherin is highly correlated with loss of SMAD4. The tumor suppressor function of SMAD4 lies in its capacity to mediate the effects of transforming growth factor–â superfamily signaling. Furthermore, in small intestinal adenocarcinomas, inactivating mutations of the SMAD4 gene have been observed.

Loss of E-cadherin was shown in colonic adenomas of patients with FAP, which suggests that it is an early event in the colonic adenoma-carcinoma sequence in FAP.

- Mammary carcinomas

Although virtually all cases of lobular carcinoma in situ lack E-cadherin expression, a proportion of morphologically typical invasive lobular carcinomas (ILCs) retain its expression. E-cadherin is expressed in a proportion of ILC, however, unlike ductal carcinoma, its expression seems to be of limited significance and it is usually associated with evidence of impaired integrity of the E-cadherin-catenin membrane complex. (20871222)

Diagnostic use

- mammary lobular neoplasia (23759937)

  • Loss of E-cadherin expression is recognized as a hallmark diagnostic feature of LN and invasive lobular carcinomas, and immunohistochemical (IHC) analysis using anti-E-cadherin antibodies has been proven to be a useful method to differentiate between lobular and ductal lesions.
  • The frequent use of E-cadherin IHC analysis in routine diagnostic histopathology, however, has resulted in confusion with regard to the actual value of IHC with antibodies against E-cadherin and other proteins of the cadherin-catenin complex.

Reviews

- Cavallaro U, Christofori G. Cell adhesion and signalling by cadherins and Ig-CAMs in cancer. Nat Rev Cancer. 2004 Feb;4(2):118-32. PMID: 14964308

- Bryant DM, Stow JL. The ins and outs of E-cadherin trafficking. Trends Cell Biol. 2004 Aug;14(8):427-34. PMID: 15308209

- Furukawa F, Fujii K, Horiguchi Y, Matsuyoshi N, Fujita M, Toda K, Imamura S, Wakita H, Shirahama S, Takigawa M. Roles of E- and P-cadherin in the human skin. Microsc Res Tech. 1997 Aug 15;38(4):343-52. PMID: 9297684

References

- Lobular neoplasia of the breast revisited with emphasis on the role of E-cadherin immunohistochemistry. Dabbs DJ, Schnitt SJ, Geyer FC, Weigelt B, Baehner FL, Decker T, Eusebi V, Fox SB, Ichihara S, Lakhani SR, Palacios J, Rakha E, Richardson AL, Schmitt FC, Tan PH, Tse GM, Vincent-Salomon A, Ellis IO, Badve S, Reis-Filho JS. Am J Surg Pathol. 2013 Jul;37(7):e1-11. doi : 10.1097/PAS.0b013e3182918a2b PMID: 23759937

- Clinical and biological significance of E-cadherin protein expression in invasive lobular carcinoma of the breast. Rakha EA, Patel A, Powe DG, Benhasouna A, Green AR, Lambros MB, Reis-Filho JS, Ellis IO. Am J Surg Pathol. 2010 Oct;34(10):1472-9. PMID: 20871222

- Periodic acid-schiff is superior to hematoxylin and eosin for screening prophylactic gastrectomies from CDH1 mutation carriers. Lee AF, Rees H, Owen DA, Huntsman DG. Am J Surg Pathol. 2010 Jul;34(7):1007-13. PMID: 20534996

Portfolio

  • E-cadherin and adherens junction