A Geometrically-Constrained Mathematical Model of Mammary Gland Ductal Elongation Reveals Novel Cellular Dynamics within the Terminal End Bud

Ingrid Paine, Arnaud Chauviere, John Landua, Amulya Sreekumar, Vittorio Cristini, Jeffrey Rosen, Michael T Lewis

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

Abstract

Mathematics is often used to model biological systems. In mammary gland development, mathematical modeling has been limited to acinar and branching morphogenesis and breast cancer, without reference to normal duct formation. We present a model of ductal elongation that exploits the geometrically-constrained shape of the terminal end bud (TEB), the growing tip of the duct, and incorporates morphometrics, region-specific proliferation and apoptosis rates. Iterative model refinement and behavior analysis, compared with biological data, indicated that the traditional metric of nipple to the ductal front distance, or percent fat pad filled to evaluate ductal elongation rate can be misleading, as it disregards branching events that can reduce its magnitude. Further, model driven investigations of the fates of specific TEB cell types confirmed migration of cap cells into the body cell layer, but showed their subsequent preferential elimination by apoptosis, thus minimizing their contribution to the luminal lineage and the mature duct.

Original languageEnglish (US)
Pages (from-to)e1004839
JournalPLoS Computational Biology
Volume12
Issue number4
DOIs
StatePublished - Apr 2016

Keywords

  • Animals
  • Apoptosis
  • Body Patterning
  • Cell Cycle
  • Cell Proliferation
  • Cell Size
  • Computational Biology
  • Female
  • Kinetics
  • Mammary Glands, Animal
  • Mice
  • Mice, Inbred BALB C
  • Mice, Transgenic
  • Models, Anatomic
  • Models, Biological
  • Sexual Maturation
  • Journal Article
  • Research Support, Non-U.S. Gov't

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