Depletion of Trp53 and Cdkn2a Does Not Promote Self-Renewal in the Mammary Gland but Amplifies Proliferation Induced by TNF-α

The mammary epithelium undergoes several rounds of extensive proliferation during the female reproductive cycle. Its expansion is a tightly regulated process, fueled by the mammary stem cells and these cells' unique property of self-renewal. Sufficient new cells have to be produced to maintain the integrity of a tissue, but excessive proliferation resulting in tumorigenesis needs to be prevented. Three well-known tumor suppressors, p53, p16INK4a, and p19ARF, have been connected to the limiting of stem cell self-renewal and proliferation. Here we investigate the roles of these three proteins in the regulation of self-renewal and proliferation of mammary epithelial cells. Using mammary epithelial-specific mouse models targeting Trp53 and Cdkn2a, the gene coding for p16INK4a and p19ARF, we demonstrate that p53, p16INK4a, and p19ARF do not play a significant role in the limitation of normal mammary epithelium self-renewal and proliferation, whereas in the presence of the inflammatory cytokine TNF-α, Trp53−/−Cdkn2a−/− mammary basal cells exhibit amplified proliferation. •p53, p16INK4a, and p19ARF do not limit self-renewal of mammary epithelial cells•p53, p16INK4a, and p19ARF do not limit proliferation of mammary epithelial cells•TNF-α stimulates mammary basal cell organoid formation and proliferation•Trp53−/−Cdkn2a−/− organoids are sensitized to TNF-α-induced proliferation Van Weele et al. demonstrate that combined deficiency of the tumor suppressors p53, p16INK4a, and p19ARF does not limit self-renewal and proliferation in normal murine mammary epithelial cells. They show that the inflammatory cytokine TNF-α promotes organoid formation and proliferation and sensitizes Trp53−/−Cdkn2a−/− organoids to excessive proliferation. These findings indicate that during inflammation, p53, p16INK4a, and p19ARF may limit proliferation.