A mammary-specific model demonstrates the role of the p53 tumor suppressorgene in tumor development

Although alterations in the p53 tumor suppressor gene are detected frequent ly in human breast cancers, mammary tumors are observed infrequently in p53 (null) mice. This has led to the suggestion that absence of p53 alone is no t sufficient for induction of mammary tumors. However, early death of p53(n ull) mice from thymic lymphomas may obscure tumor phenotypes that mould dev elop later. Therefore, p53(null) mammary epithelium was transplanted into c leared mammary fat pads of wild type p53 BALB/c hosts to allow long-term an alysis of mammary tumor phenotypes. Five treatments were compared for their effects on tumor incidence in hosts bearing transplants of p53(null) and p 53(wt) mammary epithelium, The treatment groups were: (1) untreated; (2) co ntinuous hormone stimulation with pituitary isografts; (3) multiple pregnan cies; (4) DMBA alone; and (5) DMBA + pituitary isografts, The tumor inciden ces in p53(null) vs p53(wt) mammary transplants for each treatment group we re 62% vs 0%, 100% vs 0%, 68% vs 0%, 60% vs 4% and 91%, vs 14%, respectivel y. The mammary tumors that developed in the p53(null) mammary epithelium we re all adenocarcinomas and were frequently aneuploid, These data demonstrat e that the absence of p53 is sufficient to cause development of mammary tum ors and that hormonal stimulation enhances the tumorigenicity of p53(null) mammary epithelium to a greater extent than DMBA exposure alone. This model provides an in situ approach to examine the molecular basis for the role o f p53 in the regulation of mammary tumorigenesis.