It is now widely accepted that elements of the cellular and tissue microenvironment are crucial regulators of cell behavior inculture and homeostasis in vivo, and that many of the same factors influence the course of tumor progression. Less well establishedis the extent to which extracellular factors actually cause cancer, and the circumstances under which this may occur. Using physiologically relevant three-dimensional culture assays and transgenic animals, we have explored how the environmentaland architectural context of cells, tissues, and organs controls mammary-specific gene expression, growthregulation, apoptosis, and drug resistance and have found that loss of tissue structure is a prerequisite for cancer progression. Here we summarize this evidence and highlight two of our recent studies. Using mouse mammary epithelial cells, we showthat exposure to matrix metalloproteinase-3 (MMP-3) stimulates production of reactive oxygen species (ROS) that destabilizethe genome and induce epithelial-mesenchymal transition, causing malignant transformation. Using a human breast cancerprogression series, we find that ADAM-dependent growth factor shedding plays a crucial role in acquisition of the malignantphenotype. These findings illustrate how normal tissue structure controls the response to extracellular signals so as topreserve tissue specificity and growth status.