Mechanisms and factors critical in regulating E-cadherin and beta-catenin expression and function in carcinomas

Defective cell-cell adhesion is among the hallmarks of cancer. Alterations in cadherin-catenin complexes likely have a major role in cell adhesion defects in carcinomas, and loss of E-cadherin expression has been found in human carcinomas arising in many different tissues. Mutations in the E-cadherin gene account for loss of protein in some carcinomas. In other tumors, such as invasive ductal breast carcinoma, loss of E-cadherin expression is commonly seen, yet E-cadherin mutations have only rarely been found. We therefore sought to characterize mechanisms and factors underlying loss of E-cadherin in invasive breast carcinoma. The generation and analysis of somatic cell hybrids resulting from pairwise fusions of breast cancer cell lines with intact E-cadherin transcription and those defective for E-cadherin transcription provided evidence of a dominant pathway extinguishing E-cadherin transcription via its proximal promoter. Characterization of specific proximal promoter elements highlighted the role of E-box elements that negatively regulated E-cadherin transcription and a GC-rich region that positively regulated E-cadherin transcription in breast cancer cell lines. The SLUG and SNAIL transcription factors repressed E-cadherin reporter constructs via the E-box elements, and the factors also repressed endogenous E-cadherin . SLUG is the more likely in vivo repressor of E-cadherin transcription, as its expression was inversely correlated with E-cadherin expression in breast cancer cell lines. The Wilms' tumor transcription factor WT1 activated E-cadherin transcription via the GC-rich element in some cell systems, but was not a critical regulator of E-cadherin in breast cancer lines.; We established an inducible system for beta-catenin activation to determine whether transient overexpression of mutant beta-catenin is sufficient for initiation and maintenance of the transformed phenotype. We found that following beta-catenin-mediated transformation, beta-catenin inactivation resulted in the absence of transcriptionally active beta-catenin-Tcf/Lef complexes. However, cells retained a transformed phenotype and some target genes remained overexpressed. These findings suggest transient deregulation of beta-catenin-Tcf/Lef signaling may lead to lasting alterations in the cellular gene expression patterns, and additional data indicated this might be through persistent alterations in chromatin structure. Continued characterization of the role of E-cadherin and beta-catenin alterations in carcinomas should positively impact diagnosis and management of cancer patients.