Novel p53 mutants selected in BRCA-associated tumours which dissociate transformation suppression from other wild-type p53 functions.
Inheritance of germ-line mutant alleles of BRCA1 and BRCA2 confers a markedly increased risk of breast cancer and we have previously reported a higher incidence of p53 mutations in these tumours than in grade matched sporadic tumours. We have now characterized these p53 mutants. The results of these studies identify a novel class of p53 mutants previously undescribed in human cancer yet with multiple occurrences in BRCA-associated tumours which retain a profile of p53-dependent activities in terms of transactivation, growth suppression and apoptosis induction which is close or equal to wild-type. However, these mutants fail to suppress transformation and exhibit gain of function transforming activity in rat embryo fibroblasts. These mutants therefore fall into a novel category of p53 mutants which dissociate transformation suppression from other wild-type functions. The rarity of these mutants in human cancer and their multiple occurrence in BRCA-associated breast tumours suggests that these novel p53 mutants are selected during malignant progression in the unique genetic background of BRCA1- and BRCA2-associated tumours.
Smith
P D
PD
Institute of Cancer Research, Haddow Laboratories, Sutton, Surrey, UK.
Crossland
S
S
Parker
G
G
Osin
P
P
Brooks
L
L
Waller
J
J
Philp
E
E
Crompton
M R
MR
Gusterson
B A
BA
Allday
M J
MJ
Crook
T
T
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein; D001943:Breast Neoplasms / Q000235:genetics*; D002277:Carcinoma / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics; D004622:Embryo, Mammalian / Q000166:cytology; D005260:Female; D005347:Fibroblasts; D015972:Gene Expression Regulation, Neoplastic; D005816:Genetic Complementation Test; D006801:Humans; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics*; D051381:Rats; D013489:Suppression, Genetic; D014157:Transcription Factors / Q000235:genetics*; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
D019313:BRCA1 Protein; D024682:BRCA2 Protein; C493956:CDKN1A protein, human; C493958:Cdkn1a protein, rat; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D009363:Neoplasm Proteins; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53