Laminin-1 mediates epigenetic control of the epithelial cadherin for breast cancer cells in three-dimensional culture

During the course of tumor metastasis, individual cells detach from the primary tumor and relocate to distant tissues. Factors within distant tissues promote metastatic colonization whereby the migratory cells revert back to a more epithelial phenotype, re-establishing cell-cell and cell-matrix attachment. The regulation of the epithelial adhesion molecule, E-cadherin, and subsequent cell-cell adhesion appear to be critical in determination of the malignant cell phenotype. In many metastatic neoplasias, E-cadherin expression is under epigenetic control through promoter methylation of CpG islands, which is maintained by DNA methyltransferase 1 (DNMT1). The tissue microenvironment is thought to be instrumental in driving this process; however the molecular mechanisms for decreasing promoter methylation and increasing E-cadherin expression remain largely uncharacterized. Changes in cell morphology and the formation of cell-cell adhesions in vitro suggests that extracellular matrix proteins may be important in modulating tumorigenesis giving extracellular matrix proteins a role in this process, and the basement membrane protein, laminin-1, appears to mediate these activities. Here, we utilize a three-dimensional culture model to demonstrate that laminin-1 can regulate DNMT1 expression and subsequent methylation of the E-cadherin promoter; commensurate with E-cadherin expression is the formation of cell-cell adhesions and down-regulation of the mesenchymal protein, cadherin 11. These effects are reversed when the malignant cells are cultured in the presence of the interstitial matrix protein, collagen I, resulting in a scattered, mesenchymal phenotype. Thus, we propose that laminin-1 modulates changes in cadherin composition by regulating DNA methyltransferase 1 expression and E-cadherin promoter methylation.