A p53 network immunohistochemically-based signature to discriminate between good and poor prognosis breast cancer would have clinical relevance, given the key role of p53 in malignancy and response to therapy. Utilizing a five-protein signature of p53/mdm2/mdm4/bcl2/p21 discriminates good-prognosis and poor-prognosis patient groups, based on the functionality of the p53 network. However, the relationship of this five-protein signature to p53 mutation, the wide range of breast cancer therapies now in use and the over-70 age group remain uncertain. Nonetheless, confirmation of the signature in two independent series suggests that this approach should be considered in further case series and in the context of clinical trials.