Alteration in composition of keratin intermediate filaments in a model of breast cancer progression and the potential to reverse hallmarks of metastasis

摘要

BACKGROUND: In breast cancer the development of metastasis is a major turning point in the treatment and outcome of the disease. Throughout tumour development, and especially in the development of metastasis, epithelial mesenchymal transition takes place. During this transformation into a mesenchymal phenotype, the tumour cells undergo a series of structural changes. The loss of structural integrity and adoption of mesenchymal filaments enables cells to detach from the epithelial cell layer and metastasise. Keratins form the intermediate filaments of the cytoskeleton and provide scaffold structures within cells. During cancer progression the intermediate filaments are reorganised, and dramatic changes are seen in their protein components. Keratins K8, K18, K19 and vimentin are intermediate filament proteins with altered expression profiles during tumour development.nMETHOD: We have used in vivo and in vitro models to analyse changes in intermediate filament proteins. Antibody-based methods were used to study K8 levels and proteomic analysis to profile the protein content of metastatic breast cancer cell variants.nRESULTS: K8 expression declines as human breast tumours progress into an invasive phenotype. Analysis of IF proteins indicated altered expression profiles of K8, K18, K19 and vimentin, with K8, K18, K19 expressed in high levels in the T47D and MCF-7 cell lines, whereas the highly metastatic