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Mutant p53 R270H gain of function phenotype in a mouse model for oncogene‐induced mammary carcinogenesis
Author(s) -
Heinlein Christina,
Krepulat Frauke,
Löhler Jürgen,
Speidel Daniel,
Deppert Wolfgang,
Tolstonog Genrich V.
Publication year - 2007
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.23317
Subject(s) - mutant , carcinogenesis , biology , genetically modified mouse , phenotype , cancer research , transgene , wild type , loss function , tumor progression , mammary tumor , missense mutation , mutation , oncogene , metastasis , cancer , gene , breast cancer , genetics , cell cycle
In human breast cancer, mutations in the p53 gene are associated with poor prognosis. However, analysis of patient data so far did not clarify, whether missense point mutations in the p53 gene, in addition to causing loss of wild‐type p53 function, also confer a gain of function phenotype to the encoded mutant p53. As heterogeneity of patient material and data might obscure a clear answer, we studied the effects of a coexpressed mutant p53 R270H in transgenic mice in which SV40 early proteins initiate the development of mammary adenocarcinoma (WAP‐T mice). In such tumors the endogenous wild‐type p53 is functionally compromised by complex formation with SV40 T‐antigen, thereby constituting a loss of wild‐type p53 function situation that allowed analysis of the postulated gain of function effects of mutant p53 R270H . We found that mutant p53 R270H in bi‐transgenic mice enhanced the transition from intraepithelial neoplasia to invasive carcinoma, resulting in a higher frequency of invasive carcinoma per gland and per mouse, a more severe tumor phenotype, and more frequent pulmonary metastasis. Surprisingly, mutant p53 R270H in this system does not increase genomic instability. Therefore, other postulated gain of function activities of mutant p53 must be responsible for the effects described here. © 2007 Wiley‐Liss, Inc.