Altered-function p53 missense mutations identified in breast cancers can have subtle effects on transactivation.
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.
Jordan
Jennifer J
JJ
Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, North Carolina 27709, USA.
Inga
Alberto
A
Conway
Kathleen
K
Edmiston
Sharon
S
Carey
Lisa A
LA
Wu
Lin
L
Resnick
Michael A
MA
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*
D016159:Tumor Suppressor Protein p53; D005690:Galactose
Mol Cell Biol. 2002 Dec;22(24):8612-25
12446780
Oncogene. 1998 Aug 6;17(5):651-6
9704931
Oncogene. 2001 Jun 14;20(27):3573-9
11429705
Mol Cell. 2003 Oct;12(4):1015-27
14580351
Adv Exp Med Biol. 2007;608:70-86
17993233
Oncogene. 2007 Apr 2;26(15):2191-201
17401428
Int J Cancer. 1999 Dec 22;84(6):587-93
10567903
Int J Cancer. 1994 May 15;57(4):498-503
7910151
Oncogene. 2007 Apr 2;26(15):2226-42
17401432
Cancer Lett. 2007 Mar 18;247(2):353-5; author reply 356-8
16750598
Mol Cell Biol. 2007 Dec;27(23):8284-95
17908790
EMBO J. 1996 Feb 15;15(4):827-38
8631304
J Cell Biochem. 2004 Nov 15;93(5):878-86
15449312
Cancer Res. 2001 Mar 15;61(6):2505-12
11289122
Proc Natl Acad Sci U S A. 2005 Sep 20;102(38):13550-5
16141321
Nat Genet. 2001 Jul;28(3):266-71
11431698
Cancer Res. 2002 Apr 1;62(7):1987-95
11929815
Oncogene. 2007 Apr 2;26(15):2202-11
17401429
Biol Chem. 2009 Oct;390(10):951-63
19453282
Genes Chromosomes Cancer. 2006 Nov;45(11):1033-40
16897746
Cancer Res. 1994 Mar 1;54(5):1298-304
8118819
Proc Natl Acad Sci U S A. 2008 Jul 29;105(30):10360-5
18650397
Lancet. 1997 Aug 30;350(9078):638-9
9288052
Proc Natl Acad Sci U S A. 2006 Oct 10;103(41):15056-61
17015838
Int J Cancer. 1998 Dec 9;78(6):766-74
9833771
Clin Cancer Res. 2007 Apr 15;13(8):2329-34
17438091
Methods Enzymol. 2006;409:329-45
16793410
EMBO J. 1998 Apr 1;17(7):1847-59
9524109
Ann Oncol. 2007 Jun;18(6):997-1003
17369602
Proc Natl Acad Sci U S A. 2003 Aug 19;100(17):9934-9
12909720
J Mol Biol. 2003 Mar 28;327(3):699-709
12634062
J Natl Cancer Inst. 1996 Feb 21;88(3-4):173-82
8632491
Clin Cancer Res. 2000 Jan;6(1):50-6
10656431
Oncogene. 1998 May 14;16(19):2527-39
9627118
Trends Cell Biol. 2007 Jun;17(6):286-91
17481900
Nature. 2000 Aug 17;406(6797):747-52
10963602
Cancer Lett. 2008 Mar 8;261(1):21-5
18248785
Biochemistry. 2003 Mar 4;42(8):2396-403
12600206
Cancer Res. 2003 Oct 15;63(20):6643-50
14583457
Oncogene. 1998 Mar 12;16(10):1369-72
9546439
Oncogene. 2000 Mar 2;19(10):1245-56
10713666
Clin Cancer Res. 2006 Feb 15;12(4):1157-67
16489069
Clin Cancer Res. 2007 Jul 1;13(13):3789-95
17606709
Breast Cancer Res Treat. 2006 Sep;99(1):97-101
16541312
Cancer Res. 1994 Sep 15;54(18):4855-78
8069852
Cancer Res. 2001 May 15;61(10):4092-7
11358831
Oncogene. 2002 Mar 7;21(11):1641-8
11896595
Hum Mutat. 2006 Feb;27(2):163-72
16395672
Clin Cancer Res. 2003 Nov 15;9(15):5582-8
14654539
Science. 1994 Jul 15;265(5170):346-55
8023157
Hum Mutat. 2007 Jun;28(6):622-9
17311302
Breast Cancer Res. 2006;8(4):R38
16846527
Cell. 1989 Jun 30;57(7):1083-93
2525423
Proc Natl Acad Sci U S A. 2008 Aug 12;105(32):11264-9
18685109
Br J Cancer. 2002 Oct 21;87(9):1019-26
12434295
Oncogene. 2008 Jul 3;27(29):4013-23
18278067
Cell. 2004 Dec 17;119(6):847-60
15607980
Oncogene. 2008 May 15;27(22):3165-75
18071313
J Biol Chem. 2005 Apr 22;280(16):16030-7
15703170
J Biol Chem. 2004 Jan 2;279(1):348-55
14559903
Breast Cancer Res. 2007;9(3):R30
17504517
PLoS Genet. 2008 Jun 27;4(6):e1000104
18714371
J Natl Cancer Inst. 2005 Aug 3;97(15):1137-42
16077072
Carcinogenesis. 2004 Sep;25(9):1551-7
15231688
Genes Dev. 2005 Sep 15;19(18):2122-37
16131611
Breast Cancer Res Treat. 2003 May;79(1):37-46
12779080
BMC Cancer. 2006 Dec 06;6:276
17150101
Nucleic Acids Res. 1992 Apr 11;20(7):1539-45
1579447
Genes Dev. 1996 May 1;10(9):1054-72
8654922
Mol Cell Biol. 2006 Mar;26(6):2297-308
16508005
Genes Dev. 2008 May 15;22(10):1337-44
18483220
Cell. 2004 Dec 17;119(6):861-72
15607981
Cancer Cell. 2006 Dec;10(6):529-41
17157792
Cancer Lett. 2007 Jan 8;245(1-2):96-102
16494995
Hum Mutat. 2003 Mar;21(3):313-20
12619118
Nat Med. 2005 Dec;11(12):1306-13
16286925
Nat Rev Cancer. 2001 Oct;1(1):68-76
11900253
JAMA. 2006 Jun 7;295(21):2492-502
16757721
Nat Struct Biol. 2002 Jan;9(1):12-6
11753428
Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8424-9
12826609