Cadherins and the mammary gland

Abstract

Cadherin cell-cell adhesion proteins are critical for the formation of tissues from single cells. E-and P-cadherin play important roles in the architecture and function of the normal mammary gland. In breast cancers, the expression, or lack thereof, of E-cadherin can differentiate tumor types, whereas the misexpression of either P-cadherin or N-cadherin can be a marker of poor prognosis or increased malignancy, respectively. Additional research is needed to more precisely define the roles of both classical and desmosomal cadherins and their downstream signaling events, in the development and malignant behavior of breast cancers. J. Cell. Classical and desmosomal cadherins mediate cell-cell adhesion and are members of the larger cadherin protein family. They are single-pass transmembrane proteins whose extracellular domain promotes cell-cell adhesion, while the intracellular domain interacts with cytoplasmic proteins, including the a-, b-, g-catenins (also known as plakoglobin) and p120 in the case of classical cadherins. a-and b-catenin (alternatively plakoglobin) link classical cadherins directly and indirectly to the actin cytoskeleton, whereas plakoglobin, desmoplakins, and plakophilins link desmosomal cadherins to the intermediate filament cytoskeleton. By virtue of their homophilic interaction and cell-type specific expression, the classical cadherins initiate cell-cell adhesion and promote cell sorting, whereas the desmosomal cadherins provide added strength to cell-cell interactions. The p120 catenin is thought to regulate clustering of classical cadherins in the plane of the membrane and to regulate the strength of cadherin cell adhesion in both positive and negative ways. In addition to playing important roles in cell adhesion, p120 and b-catenin interact with nuclear

In breast carcinoma dysadherin expression is correlated with invasiveness but not with E-cadherin

“…Thus, in ductal carcinoma E-cadherin is expressed, albeit in reduced levels and aberrant cellular locations. Although E-cadherin correlates inversely with the grade of the tumour, reduced E-cadherin expression is not adequate to predict clinical outcome and there are contradictory studies on the association between E-cadherin and survival (Knudsen and Wheelock, 2005). Moreover, it has been reported that in other breast cancers with known poor prognosis, such as inflammatory breast cancer, there is overexpression of E-cadherin (Knudsen and Wheelock, 2005).…”

“…Although E-cadherin correlates inversely with the grade of the tumour, reduced E-cadherin expression is not adequate to predict clinical outcome and there are contradictory studies on the association between E-cadherin and survival (Knudsen and Wheelock, 2005). Moreover, it has been reported that in other breast cancers with known poor prognosis, such as inflammatory breast cancer, there is overexpression of E-cadherin (Knudsen and Wheelock, 2005). An interesting concept is that possibly the reduction of E-cadherin expression in breast carcinomas, other than lobular, is transient, due to epigenetic modifications.…”

“…This loss is an early event affecting not only lobular carcinoma in situ but even atypical lobular neoplasia (Mastracci et al, 2005). This silencing of E-cadherin is attributed to genetic as well as epigenetic events (Knudsen and Wheelock, 2005;Mastracci et al, 2005). In approximately 50% of lobular carcinomas loss of E-cadherin involves LOH at the chromosomal region of 16q, which includes the E-cadherin gene CDH1 locus and mutations in the remaining allele (Kanai et al, 1994;Vos et al, 1997;Huiping et al, 1999;Knudsen and Wheelock, 2005;Mastracci et al, 2005).…”

“…The demonstration of lack of E-cadherin expression in lobular neoplasms has had a sound impact with practical applications (Mastracci et al, 2005) In about half of lobular carcinomas, loss of E-cadherin involves genetic changes, that is loss of heterozygosity (LOH) at 16q22.1, while in the other half epigenetic events are involved (Knudsen and Wheelock, 2005;Mastracci et al, 2005). Ductal carcinomas, on the other hand, express E-cadherin, albeit in reduced levels and/or in abnormal cellular locations (Knudsen and Wheelock, 2005). Reduction/loss of E-cadherin has been associated with the development and progression of many epithelial neoplasms.…”

“…In breast the scenario is more complicated, since lobular carcinoma, that typically does not express E-cadherin has a more favourable outcome than ductal carcinoma, which in general expresses E-cadherin. Furthermore, there are contradictory data on the possible association between E-cadherin expression and high-grade tumours with increased metastatic potential (Oka et al, 1993;Charpin et al, 1997;Heimann et al, 2000;Gillett et al, 2001;Parker et al, 2001;Elzagheid et al, 2002;Gupta et al, 2003;Knudsen and Wheelock, 2005;Rakha et al, 2005). It is clear that there are pieces missing from the puzzle of adhesion molecules and breast carcinoma.…”