Tumor suppressor p53 mutations and breast cancer: a critical analysis.

Alterations in the tumor suppressor gene p53 are the most commonly identified changes in cancer, including neoplasia of the breast. The activity of p53 is regulated post-translationally. Phosphorylation state, subcellular localization, and interaction with any of a number of cellular proteins are likely to influence the function of p53. The exact effect of p53-mediated growth suppression seems to be cell-type specific but appears to be directly related to the ability of p53 to act as a specific transcriptional activator. The role that transcriptional repression plays in the function of WT p53 is less clear. It is also possible that p53 has a more direct activity in DNA replication and repair. Most documented p53 mutations result in single amino acid substitutions which may confer one or more of a spectrum of transforming abilities on the protein. Mutation may lead to nuclear accumulation of p53 protein; however, inactivation of p53 by nuclear exclusion and interaction with the mdm2 protein also appear to be important in tumorigenesis. Used in conjunction with other established factors, accumulation of cellular p53 may be a useful prognostic indicator in breast cancer. A syngeneic mouse model system yielded evidence that p53 mutations are important in the early, preneoplastic stages of mammary tumorigenesis. This murine system may provide the ability to investigate the functions of p53 in the early stages of breast cancer which are technically difficult to examine in the human system.