Lattice-based model of ductal carcinoma in situ suggests rules for breast cancer progression to an invasive state.

Ductal carcinoma in situ (DCIS) is a heterogeneous group of non-invasive lesions of the breast that result from abnormal proliferation of mammary epithelial cells. Pathologists characterize DCIS by four tissue morphologies (micropapillary, cribriform, solid, and comedo), but the underlying mechanisms that distinguish the development and progression of these morphologies are not well understood. Here we explored the conditions leading to the emergence of the different morphologies of DCIS using a two-dimensional multi-cell lattice-based model that incorporates cell proliferation, apoptosis, necrosis, adhesion, and contractility.

Host epithelial geometry regulates breast cancer cell invasiveness.

Breast tumor development is regulated in part by cues from the local microenvironment, including interactions with neighboring nontumor cells as well as the ECM. Studies using homogeneous populations of breast cancer cell lines cultured in 3D ECM have shown that increased ECM stiffness stimulates tumor cell invasion. However, at early stages of breast cancer development, malignant cells are surrounded by normal epithelial cells, which have been shown to exert a tumor-suppressive effect on cocultured cancer cells.

Regulation of Epithelial-Mesenchymal Transition by Transmission of Mechanical Stress through Epithelial Tissues.

Epithelial-mesenchymal transition (EMT) is a phenotypic shift wherein epithelial cells lose or loosen attachments to their neighbors and assume a mesenchymal-like morphology. EMT drives a variety of developmental processes, but may also be adopted by tumor cells during neoplastic progression. EMT is regulated by both biochemical and physical signals from the microenvironment, including mechanical stress, which is increasingly recognized to play a major role in development and disease progression.

Snail1, Snail2, and E47 promote mammary epithelial branching morphogenesis.

Several E-box-binding transcription factors regulate individual and collective cell migration and enhance the motility of epithelial cells by promoting epithelial-mesenchymal transition (EMT). Here, we characterized the role of a subset of these transcription factors and the EMT proteome in branching morphogenesis of mammary epithelial tissues using a three-dimensional organotypic culture model of the mammary duct. We found that the transcription factors Snail1, Snail2, and E47 were transiently upregulated at branch sites; decreasing the expression of these transcription factors inhibited branching.

Mammary branch initiation and extension are inhibited by separate pathways downstream of TGFβ in culture.

During the branching morphogenesis process that builds epithelial trees, signaling from stimulatory and inhibitory growth factors is integrated to control branch initiation and extension into the surrounding stroma. Here, we examined the relative roles played by these stimulatory and inhibitory signals in the patterning of branch initiation and extension of model mammary epithelial tubules in culture. We found that although several growth factors could stimulate branching, they did not determine the sites at which new branches formed or the lengths to which branches extended.