Chalmers Conferences, 9th European Conference on Mathematical and Theoretical Biology

Breast Cancer and TGFb signaling
Gianluca Ascolani

Last modified: 2014-04-05


Breast cancer has been the most common cancer in Europe since 1997, and the chance of a woman having invasive breast cancer during her life is about 1 in 8. It is known that the bone tissue is the preferred niche of breast cancer colonization because of its richness in Transforming Growth Factor Beta (TGFb). The TGFb family of cytokines controls numerous cellular responses, including proliferation, differentiation, apoptosis and migration, and it has a key player role in the development and evolution of cancer.

Due to the particular geometry of the breast lobular ducts composed by a simple cuboidal epithelial sheet, we present a two dimensional square lattice cellular automaton model for the dynamics and the cyclic cascades of the TGFb.    

The TGFb is always produced as an inactive cytokine that cannot bind to its receptor and function unless the latent complex is somehow activated. This regulation provides a complex control of TGFb function, thereby ensuring that its potent effects are produced in appropriate locations and times. The TGFb stabilizes the tissue functionality by killing malfunctioning cells, but it needs cells to be synthesized and activated.

The inactive TGFb is secreted by cells in the surrounding extracellular matrix (ECM). In the ECM, the molecule begins to diffuse until it sticks to the fibrous matrix close to the synthesizing cell. The TGFb is activated by fragmentation of the latent component due to weak oscillating cells grasping the TGFb and tearing it off. The active TGFb diffuses through the ECM, and when close to a cell, the cytokine binds with the cell receptors. The internalized TGFb interacts with cytoskeleton, epithelial cadherins (E-cad) and integrins producing uncoupling of cell-to-cell connections and consequently, abrupt cell oscillations.

The diffusion of active TGFb causes nonlocal coupling between cells via paracrine signaling, nevertheless, this signal has a limited spatial range of action given by the finite quantity of available TGFb and degradation of the cytokine. On the other hand, cells under the effect of internalized TGFb will activate additional TGFb extending further in space the TGFb signaling. The propagation/activation of this molecule is, on one side, counterbalanced by the cell death induced by the internalization of TGFb and on the other side, it is potentially restored by cell proliferation and E-cad links formation.

Cell density, latent TGFb concentration and active TGFb concentration are coupled scalar quantities. Depending on the range and strength of the coupling, an initial perturbation in the TGFb activation can provoke the propagation of the TGFb apoptotic signal which can have limited effect in space, or can involve all the system, and the signal can self-sustain the perturbation in time, or damp it down.

We study the spatio-temporal effects of TGFb in a geometrical space resembling the breast lobular duct, and we analyze different scenarios which are of interest to maintain the homeostatic regulation of the tissue and to reproduce breast cancer early stages.


breast cancer; Transforming Growth Factor beta; cellular automaton