Reversion of the Malignant Phenotype of Human Breast Cells in Three-Dimensional Culture and In Vivo by Integrin Blocking Antibodies

摘要: In a recently developed human breast cancer model, treatment of tumor cells in 3-dimensional culture with inhibitory β1-integrin antibody or its Fab fragments led to striking morphological and functional reversion normal phenotype. A stimulatory proved be ineffective. The newly formed reverted acini re-assembled basement membrane re-established E-cadherin–catenin complexes, re-organized their cytoskeletons. At the same time they downregulated cyclin D1, upregulated p21cip,waf-1, stopped growing. Tumor treated injected into nude mice had significantly reduced number size tumors mice. tissue distribution other integrins was also normalized, suggesting existence intimate interactions between different integrin pathways as well adherens junctions. On hand, nonmalignant when either α6 β4 function altering antibodies continued grow, disorganized colony morphologies resembling untreated colonies. This shows significant role α6/β4 heterodimer directing polarity structure. observed phenotypes were reversible disassociated removed. Our results illustrate that extracellular matrix receptors dictate phenotype mammary epithelial cells, thus this model system is dominant over cellular genotype.