GADD45A and breast cancer: Once immortalized, Atf-2+/− cells are less able to induce apoptosis in response to hypoxia, to which solid tumors such as mammary tumors are exposed, via the down-regulation of the apoptosis-related genes, including Gadd45α. Consistent with these data, the knockout of Atf-2 in the basal layer of the epidermis resulted in an increase in the incidence and prevalence of papilloma development when subjected to a two-stage skin carcinogenesis protocol using DMBA/TPA (Bhoumik et al. 2008).