Taken together, our results demonstrate a role for TP53 in the EMT and differentiation of mammary epithelia, which is closely linked to the regulation of alternative isoforms of TP63. This role of TP53 may explain the prevalence of sarcomas in Trp53-deficient animal models and Li-Fraumeni syndrome patients, and shed light on the mechanisms underlying observed differences in TP53 mutation spectra between lumenal and basal breast cancers. Here, TP63 is linked to breast cancer.