Mutations in exons 5-8 of the p53 gene, independent of their type and location, are associated with increased apoptosis and mitosis in invasive breast carcinoma

In breast cancer, mutations located in the zinc-binding functional domains of the p53 gene have been reported to predict a worse prognosis and a worse response to treatment with doxorubicin, compared with mutations in other p arts within exons 5-8 of the gene. Similarly, mutations in residues of p53 that directly contact DNA have been associated with a poor prognosis. To in vestigate whether these specific p53 mutations are associated with differen ces in the rate of apoptosis and/or mitosis, or expression of the anti-apop totic Bcl-2 protein, these parameters were evaluated in 89 invasive breast cancers,vith a confirmed p53 mutation in exons 5-8 and in 99 tumours withou t a p53 mutation in exons 5-8, Neither mutations located in the zinc-bindin g functional domains nor mutations in residues that directly contact DNA we re associated with alterations in mitotic or apoptotic activity. However, c ompared with the wild-type p53 tumours, both apoptotic and mitotic indices showed an approximately two-fold increase in the mutant p53 group (p<0.001) . The presence of a p53 mutation was also associated with the presence of t umour necrosis (p<0.001), high tumour grade (p<0.001) and low expression of Bcl-2 (p<0.001). Our data support the concept that in invasive breast carc inoma, loss of p53 function is involved in enhanced proliferation rather th an decreased apoptosis and that the resulting acceleration of cell turnover may enhance clonal evolution and tumour progression. Copyright (C) 1999 Jo hn Wiley & Sons, Ltd.