Development of a Three Dimensional, Lattice-free Multiscale Model of the Mammary Terminal End Bud

The terminal end bud (TEB) is a bulbous structure composed of highly proliferative cells that is responsible for mammary gland development during the pubertal stage. This is a highly organized process, involving cellular differentiation hierarchies regulated by endocrine and paracrine signaling. Here, we present development of a lattice-free, three dimensional multiscale agent based model of the TEB to study the effects of cellular phenotypic hierarchies, endocrine and paracrine signaling, and proliferation demographics on pubertal mammary gland development. Cells in the TEB experience complex physical interaction during the active growth involved in pubertal ductal elongation, which we represent mathematically based on the physical forces involved in cell-cell and cell-microenvironment interactions. We observe that maximum ductal elongation rates are achievable due to each progenitive phenotype cell only undergoing a couple proliferation cycles before losing the progenitive capability, and that molecular signaling is necessary to restrict ductal elongation to biologically relevant rates. Cellular proliferation and growth is sufficient to achieve these elongation rates in the absence of other cellular behaviors such as migration or conformational changes. This model serves as a valuable tool to gain insights into the cell population dynamics of mammary gland development, and can serve as a foundation to study the early stages of breast cancer development based on endocrine-mediated phenotypic population shifts.