It is widely accepted that E-cadherin expression is suppressed in metastatic cancer cell. However, there are two possibilities in vivo underlying the down-regulation of E-cadherin;
1) Tumor cells undergo epithelial-mesenchymal transition, thereby decreasing E-cadherin expression level.
2) The promoter region of gene encoding E-cadherin is methylated and this epigenetic alteration is responsible for down-regulation of E-cadherin
Which theory is more likely in vivo (not in vitro)?
E-cadherin suppresion in tumor cells might be due to increased expression of matrix metalloproteinases (specifically MMP-2 and MMP-9). Increased expression of MMPs is responsible for degradation of extracellular matrix. MMPs also triggers the expression of EMT markers, such as Snail, Twist, and slug which is responsible for down-regulation E-cadherin expression that facilitate the acquirement of invasive growth properties in cancer cells.
I would not rule out the possibility that the E cadherin gene is particularly susceptible to inactivating mutations. We have seen this in the metastases of several GI and GU cancer types with or without EMT pathway activation. So there may be a direct effect on the gene as well.
Cancer cells have inherent misregulation of gene networks/programs. Though one cannot exclude the possibility of mutations in the Ecad gene body that may affect transcript or protein levels/trafficking/function, I would most readily believe that epigenetic regulation is the most common cause of Ecad suppression. Further, at the epigenetic level it is likely more complex than promoter methylation and involves other cis regulatory modules.
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