E-cadherin and loss of heterozygosity at chromosome 16 in breast carcinogenesis: different genetic pathways in ductal and lobular breast cancer?

The homotypic cellular adhesion molecule E-cadherin is one of the most vital components in the cell. It is implicated as a key player in different cellular processes including development, morphology, polarity, migration and tissue integrity [1]. E-cadherin is a glycoprotein with an extracellular domain that interacts with E-cadherin molecules on adjacent cells, thereby establishing adhesion between epithelial cells. The intracellular domain is associated with a complex of proteins called catenins, which anchor E-cadherin to the actin cytoskeleton.In various carcinomas, plasma membrane associated E-cadherin protein expression is decreased or even absent. There is transcriptional regulation of this molecule for which a number of factors have been implicated, including promotor hypermethylation [2,3], and several proteins that regulate E-cadherin transcription, especially Snail-1 [4], SIP-1 [5] and integrin-linked kinase [6]. Mutational inactivation of the E-cadherin gene CDH1 has been reported in diffuse gastric cancer and lobular breast cancer [7]. Both these tumour types have a characteristic diffuse growth pattern with loss of cellular coherence that is in accordance with the adhesion function of the absent E-cadherin protein.The wild type CDH1 allele is missing in most lobular tumours due to loss of heterozygosity (LOH) at chromosome 16q [8], thereby presenting a classical example of Knudson's two-hit hypothesis on the inactivation of tumour suppressor genes. The more frequent ductal breast carcinomas also show frequent LOH at 16q; however, these tumours do not have mutational inactivation of the retained CDH1 allele [9]. Given the importance and widespread involvement of E-cadherin in tumorigenic processes, it is tempting to assume that a decrease in E-cadherin activity in ductal carcinomas is selected for and is reflected by LOH at 16q. Indeed, haploinsufficiency has now been acknowledged as a true mechanism for tumour suppressor gene inactivation [10]. However