title: 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.
abstract: 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 parts 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 investigate whether these specific p53 mutations are associated with differences in the rate of apoptosis and/or mitosis, or expression of the anti-apoptotic Bcl-2 protein, these parameters were evaluated in 89 invasive breast cancers with a confirmed p53 mutation in exons 5-8 and in 99 tumours without a p53 mutation in exons 5-8. Neither mutations located in the zinc-binding functional domains nor mutations in residues that directly contact DNA were associated with alterations in mitotic or apoptotic activity. However, compared 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 tumour 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 carcinoma, loss of p53 function is involved in enhanced proliferation rather than decreased apoptosis and that the resulting acceleration of cell turnover may enhance clonal evolution and tumour progression.
authors.affiliation: Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: H J
authors.initials: HJ
authors.lastname: van Slooten
authors.forename: M J
authors.initials: MJ
authors.lastname: van De Vijver
authors.forename: A L
authors.initials: AL
authors.lastname: Borresen
authors.forename: J E
authors.initials: JE
authors.lastname: Eyfjörd
authors.forename: R
authors.initials: R
authors.lastname: Valgardsdóttir
authors.forename: S
authors.initials: S
authors.lastname: Scherneck
authors.forename: J M
authors.initials: JM
authors.lastname: Nesland
authors.forename: P
authors.initials: P
authors.lastname: Devilee
authors.forename: C J
authors.initials: CJ
authors.lastname: Cornelisse
authors.forename: J H
authors.initials: JH
authors.lastname: van Dierendonck
mesh_terms: D017209:Apoptosis / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics*; D016009:Chi-Square Distribution; D004252:DNA Mutational Analysis; D005091:Exons; D005260:Female; D016368:Frameshift Mutation; D017353:Gene Deletion; D019254:Genes, bcl-2; D016158:Genes, p53 / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008875:Middle Aged; D008940:Mitotic Index / Q000235:genetics*; D009154:Mutation; D020125:Mutation, Missense