title: Altered-function p53 missense mutations identified in breast cancers can have subtle effects on transactivation.
abstract: Mutations of the sequence-specific master regulator p53 that alter transactivation function from promoter response elements (RE) could result in changes in the strength of gene activation or spectra of genes regulated. Such mutations in this tumor suppressor might lead to dramatic phenotypic changes and diversification of cell responses to stress. We have determined "functional fingerprints" of sporadic breast cancer-related p53 mutants, many of which are also associated with familial cancer proneness such as the Li-Fraumeni syndrome and germline BRCA1/2 mutant-associated cancers. The ability of p53, wild-type and mutants, to transactivate from 11 human target REs has been assessed at variable expression levels using a cellular, isogenomic yeast model system that allows for the rapid analysis of p53 function using a qualitative and a quantitative reporter. Among 50 missense mutants, 29 were classified as loss of function. The remaining 21 retained transactivation toward at least one RE. At high levels of galactose-induced p53 expression, 12 of 21 mutants that retain transactivation seemed similar to wild-type. When the level of galactose was reduced, transactivation defects could be revealed, suggesting that some breast cancer-related mutants can have subtle changes in transcription. These findings have been compared with clinical data from an ongoing neoadjuvant chemotherapy treatment trial for locally advanced breast tumors. The functional and nonfunctional missense mutations may distinguish tumors in terms of demographics, appearance, and relapse, implying that heterogeneity in the functionality of specific p53 mutations could affect clinical behavior and outcome.
authors.affiliation: Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, North Carolina 27709, USA.
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Jordan
authors.forename: Alberto
authors.initials: A
authors.lastname: Inga
authors.forename: Kathleen
authors.initials: K
authors.lastname: Conway
authors.forename: Sharon
authors.initials: S
authors.lastname: Edmiston
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Carey
authors.forename: Lin
authors.initials: L
authors.lastname: Wu
authors.forename: Michael A
authors.initials: MA
authors.lastname: Resnick
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002277:Carcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D005690:Galactose / Q000378:metabolism / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D016297:Mutagenesis, Site-Directed; D020125:Mutation, Missense / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D020218:Response Elements / Q000235:genetics; D014158:Transcription, Genetic / Q000235:genetics; D015533:Transcriptional Activation / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D016159:Tumor Suppressor Protein p53; D005690:Galactose
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