Cadherin-catenin adhesion complexes play important roles by providing cell-cell adhesion and communication in different organ systems. Abnormal expression of cadherin adhesion molecules constitutes a common phenomenon in canine mammary cancer and has been frequently implicated in tumour progression. This paper summarizes the current knowledge on cadherin/catenin adhesion molecules (E-cadherin,
In canine species, spontaneous mammary tumours constitute the second most frequent neoplasia, surpassed only by skin tumours. When considering female dogs, mammary tumours represent the most common neoplasia, with malignant tumours accounting for up to 50% of cases [
Mammary tumours of the female dog are commonly associated with the development of distant metastases, which ultimately leads to morbidity and mortality. In the initial steps of this complex biological process, neoplastic cells lose intercellular adhesion in order to invade local tissues, and it is now evident that tumour invasion and progression may result from changes in cell adhesion systems. Based on sequence homology and structure, cell adhesion molecules are divided into the following families: cadherins, selectins, integrins, the immunoglobulin superfamily, and lymphocyte homing receptors, such as CD44 [
Cadherins are calcium-dependent cell-cell adhesion molecules, believed to be essential in coordinating morphogenetic cell movements and in the maintenance of normal tissue architecture [
Until now, more than 20 members of the cadherin family have been described, characterized by cell type-specific expression patterns [
Classical cadherins and their associated catenins form adhesion structures identified as adherens junctions [
Schematic overview of the classical cadherin-catenin complex. Classical cadherins (blue), which mediate calcium-dependent (red) intercellular adhesion, are composed by an extracellular domain, a transmembrane domain and a cytoplasmic domain. This one comprises a juxtamembrane domain, which binds to p120-catenin (orange), and a catenin-binding domain, which binds
Epithelial (E-) cadherin (also called uvomorulin, L-Cam, cell-Cam 120/80, or Arc-1) was the first to be identified and constitutes the prototypic member of the classical cadherin family. E-cadherin is a 120 kDa glycoprotein and is found in almost all epithelial tissues [
The function and strength of cadherin-mediated adhesion depends on its dynamic association with catenins [
Besides being a cytoplasmic protein involved in linking cadherin family receptors to the actin cytoskeleton [
P120-catenin interacts directly with the juxtamembrane domain (JMD) of cytoplasmic tail and is regulated by tyrosine kinases, modulating cadherin intracellular trafficking, stability, adhesive capacity, and cell motility. Besides the interaction with p120 catenin, JMD supports lateral clustering and adhesive strengthening of cadherin complexes [
Cell adhesion is a dynamic process regulated at various levels, including gene transcription, protein stability, and posttranslational modifications, in particular by phosphorylation of
In normal canine mammary gland, E-cadherin and P-cadherin show a distinct pattern of expression. E-cadherin and
Immunohistochemical reactivity to adhesion molecules in canine mammary gland tissues. Normal mammary gland stained with antibodies to E-cadherin (a),
Despite the prolific studies in the human setting regarding cell adhesion implications in cancer, there are still few publications available in canine species. So, the specific role of cadherin-mediated cell adhesion in canine mammary cancer has not yet been fully revealed [
The vast majority of studies on cell adhesion involvement in tumourigenesis and invasion have focused on E-cadherin, given that this molecule is the major cadherin implicated in epithelial cell-cell adhesion, and the majority of tumours originate from epithelial cells [
There are several lines of evidence pointing out to E-cadherin tumour/invasion suppressor function, namely,
In 1997, Restucci and coworkers evaluated for the first time the immunohistochemical E-cadherin expression in canine mammary tumours, describing a reduced membranous expression in malignant neoplasia [
According to our and other studies, reduced membranous expression of E-cadherin was significantly associated with tumour histological type. Solid-type carcinomas showed frequent loss of E-cadherin expression, in contrast to tubulopapillary carcinoma type [
Human studies usually document the loss of E-cadherin in lobular carcinomas, which result from a mutational inactivation of E-cadherin gene, frequently associated with the loss of heterozygosity of the other allele [
A number of investigators, including our group, reported that reduced E-cadherin expression was associated with invasion (Figure
The analysis of E-cadherin expression in lymph node metastases was rarely reported and several patterns of expression have been described, namely, downregulation, upregulation, or similar expression levels with regard to primary lesions [
However, it is unlikely that a single molecule can determine the acquisition of a less differentiated and more invasive neoplastic phenotype and other molecules must be considered in order to understand the complex mechanisms that lead to metastasis [
The expression of E-cadherin complex partner,
In addition, reduced membranous
The prognostic significance of E-cadherin and
Although, in general, loss of E-cadherin expression correlates with undifferentiated human breast carcinomas, the available studies differ with regard to its association with survival and its value as a prognostic marker is still controversial [
Besides E-cadherin, a number of canine mammary tumours also express P-cadherin cell adhesion molecule (Figure
In canine mammary tumours, a significant association was found between P-cadherin expression and tumour histological type [
Our results are discordant with the majority of available studies in human breast cancer, which found P-cadherin significantly associated with several aggressive characteristics, such as high histological grade and proliferation, as well as with a poor prognosis [
With regard to histological types, P-cadherin is commonly identified in canine mammary carcinosarcoma and spindle cell carcinoma subtypes, as well as in human breast medullary and metaplastic carcinomas, which evokes for a basal/myoepithelial cell histogenetic origin or line of differentiation for these tumours [
In human cancer studies, high-throughput microarray technologies allowed the distinction of breast cancer molecular subtypes (luminal A and B, HER-2 overexpressing, basal-like, and claudin-low), with basal-like phenotype significantly associated with poor prognosis [
In our study, most luminal canine mammary carcinomas (ER positive) were P-cadherin negative [
A number of hypotheses have been proposed to justify the anomalous expression of P-cadherin by breast cancer cells, namely, the oncofetal properties of P-cadherin protein [
In fact, a significant correlation was recently described between P-cadherin expression and hypomethylation of a specific region of the CDH3 promoter, suggesting an important regulatory role for cytosine methylation in the aberrant expression of P-cadherin in breast cancer [
Although the biofunctional role of P-cadherin in tumour progression is far from being fully elucidated, several
Besides breast cancer, P-cadherin has been studied in several human cancers, and it seems to behave differently depending on the cancer model [
Taken together, the overall findings in canine mammary cancer suggest a possible role for E-cadherin-mediated adhesion in preventing invasion and metastasis in this animal model, corroborating human breast cancer studies. Yet, results are not consensual and larger controlled studies are required in order to definitively determine cell adhesion implication in the multifaceted metastatic process, as well as the usefulness of cadherins and catenins as valuable prognostic markers and potential therapeutic targets for canine mammary carcinomas.
The work was supported by the strategic Research Project PEst-OE/AGR/UI0772/2011 financed by the Foundation for Science and Technology (FCT).