The oncosuppressor protein p53 is a stress response protein that mediates growth suppression through cell cycle arrest or induction of apoptosis in response to DNA damage (4). Inactivation of the p53 protein in breast tumors

Background: Several factors are currently employed for prognosis assessment and treatment determination in breast cancer. An array of molecular parameters, such as p53, Her2-neu (c-erbB 2) and Cathepsin-D, are also examined to improve clinical patient management. We have conducted a statistically powerful study of the prognostic value of conventional factors and of the investigational factors p53, Her2-neu and Cathepsin-D in patients with invasive breast carcinoma, in order to compare their significance. Our analysis was extended to determine the associations of p53 and Her2-neu with risk of death and relapse among patients with and without lymph node metastases. Materials and Methods: In a set of 125 primary breast tumors, p53 and Her2-neu expression were immunohistochemically evaluated. Cathepsin-D, estrogen and progesterone receptor concentrations were determined in cytosols by a standard immunoradiometric assay. Results: Over a mean of 62 months, 49 patients (39%) had a relapse and 29 patients (23%) died. Overexpression of p53, Her2-neu and Cathepsin-D was observed in 31%, 46% and 88% of cases, respectively. Overall survival was associated with histology (hazard ratio 0.04, 95% confidence interval: 0.01, 0.49 for lobular tumors) and stage (hazard ratio 5.94, 95% confidence interval: 1.30, 27.15 for stage III samples). Disease-free survival was also related to histology (hazard ratio 0.23, 95% confidence interval: 0.08, 0.73 for lobular tumors) and stage (hazard ratio 4.27, 95% confidence interval: 1.36, 13.36 for stage III tumors). Patients with both negative nodal status and Her2-neu overexpression tended to display an elevated risk of death. Conclusion: Our results support the prognostic power of tumor histology and stage and emphasize the need for further studies on the prognostic impact of p53, Her2neu and Cathepsin-D in breast cancer. Additionally, our analysis indicates that deregulation of Her2-neu might characterize a subgroup of node-negative patients with poor prognosis who could benefit from an aggressive adjuvant therapy. Primary breast cancer (PBC) is the most common malignancy in the female population worldwide with more than a million new cases being diagnosed every year (1). Extensive studies have shown that tumor clinicopathological parameters are well established breast cancer prognostic factors and useful for treatment decision (2). Carcinogenesis represents a complex process that involves multiple changes in the controlling pathways of cell proliferation, apoptosis, invasiveness and metastatic spread (3). For this reason, much effort has been placed on the identification of novel molecular prognostic factors that alone or in combination with clinicopathological factors may improve the prediction of clinical outcome and determine the appropriate therapeutic approach. The oncosuppressor protein p53 is a stress response protein that mediates growth suppression through cell cycle arrest or induction of apoptosis in response to DNA damage (4). Inactivation of the p53 protein in breast tumors is caused mainly by chromosomal deletion and gene mutations, although epigenetic mechanisms also exist, including mislocalization, increased degradation and inactivation through binding to amplified mdm2 (4). In breast cancer, overexpression of the growth factor receptor 2061 Correspondence to: Vassilis G. Gorgoulis, Antaiou 53 Str., Lamprini, Ano Patissia, Athens, Greece, GR-11146. Tel: ++3-016535894, Fax: ++3-01-6535894, e-mail: [email protected]