Prognostic value of P53 gene mutations in a large series of node-negative breast cancer patients.

The most important subgroup of breast cancer patients for which reliable prognostic factors are needed are women without axillary lymph node involvement. Although overall, these patients have a good prognosis, it is known that 20-30% will experience a recurrence of the disease. To determine the prognostic significance of P53 tumor suppressor gene mutation, specimens from 113 primary breast cancers were evaluated for the presence of P53 alterations, as detected by cDNA sequencing of the entire coding sequence of the gene. The median follow-up for patients was 105 months. P53 gene mutation was an independent prognostic marker of early relapse and death. Our results suggest that P53 gene mutations could be an important factor to identify node-negative patients who have a poor prognosis in the absence of adjuvant therapy. Prospective studies should be designed to determine which therapy should be performed in this subgroup of patients.

p21(WAF1/CIP1) response to genotoxic agents in wild-type TP53 expressing breast primary tumours.

Functional inactivation of the wild-type p53 protein has been described in different human cancers. Since a significant proportion of breast tumours express wild-type TP53, the p53 antiproliferative activity could be inactivated in transformed mammary epithelial cells by a mechanism independent on structural alteration of the gene. To test this hypothesis, we analysed the p53 activity in primary breast tumour cells. As a preliminary study, we demonstrated in breast adenocarcinoma cell lines that the nuclear accumulation of the inhibitor of cyclin dependent kinase p21(WAFl/CIP1), in response to adriamycin treatment, specifically reflected the activity of a functional wild-type p53 protein. Then, we used this strategy to study the p53 activity in 23 primary breast tumours. p21(WAF1/CIP1 accumulation was detected in all tumours expressing wild-type TP53. In contrast, no p21(WAF1/CIP1) response was detected in cells harboring a mutant TP53 gene. This report is the first functional study of p53 in primary breast tumours. The results demonstrate that TP53 mutation represents the only common mechanism leading to an irreversible inactivation of p53 functions in this cancer type.