Breast cancer: the protective effect of pregnancy.

It has been firmly established in epidemiological studies that early full-term pregnancy affords lifetime protection against the development of breast cancer. This phenomenon can be mimicked in rat and mouse models of mammary cancer in which the hormones estrogen and progesterone are given for 21 days. Carcinogen-induced proliferation is blocked as a consequence of hormone pretreatment. Among several genes implicated by molecular studies to be differentially expressed is the tumor suppressor gene p53. Both immunohistochemical and Western blot studies indicate that p53 protein expression is increased in hormone-pretreated mice and rats. The p53-regulated gene p21Cip1 is also increased concomitantly with p53. To test directly the causative role of p53 in conferring a protective phenotype, we examined the hormone-induced protective effect in BALB/c p53 null mammary epithelium. In the mammary epithelium, the absence of p53 gene expression abrogated the protective effect of prior pregnancy. The tumor incidence curves were superimposable in p53 null mammary epithelium that were treated with 7,12-dimethylbenzanthracene or pregnancy plus 7,12-dimethylbenzanthracene. These results demonstrate that p53 plays a pivotal role in hormone-induced protection and raises the question of the mechanisms by which the steroid hormones, estrogen and progesterone, functionally activate p53.