Figure 7.

Differential sensitivity to radiation-induced senescence and loss of growth leads to increased outgrowth of p16(-) human mammary epithelial cells during stasis. (A) Time snapshots of one representative simulation of sequential subcultures executed using the same initial conditions as in Figure 6A, but including prematurely senescent human mammary epithelial cells (HMEC) agents (labeled blue) induced by exposure to 2 Gy of X-rays. Note the earlier and more robust outgrowth of vHMEC agents (labeled green) in this simulation versus the simulation shown in Figure 6A. (B) Growing pre- and post-stasis HMEC from the same individual were exposed to the indicated doses of X-rays, then stained and evaluated for SA-βgal expression. The resulting data were then normalized to the percentage of SA-βgal(-) HMEC in the respective unirradiated populations. Fitted curves were of the form (e^(-α.D)) where D is the dose and α the fitted coefficient; R² values were >0.96 in both cases. These fitted curves were used to model radiation-induced senescence in the simulation depicted in (A). (C) Agent-based modeling was used to simulate the growth kinetics of HMEC cultures exposed to 0 or 2 Gy of X-rays. Data ± SE for five independent simulations for each condition are plotted. Note that the model predicts a shorter growth plateau in the irradiated sample, in accord with experimental observations.