Mutant p53^R270H gain of function phenotype in a mouse model for oncogene‐induced mammary carcinogenesis

Abstract

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.

Anthracyclines induce the accumulation of mutant p53 through E2F1-dependent and -independent mechanisms

“…As a consequence, the cells may become more resistant to further cycles of genotoxic therapy (Blandino et al, 1999;Bush and Li, 2002). Mutant p53 gain of function would also include cell spread, invasion and metastasis (Heinlein et al, 2008;Adorno et al, 2009;Muller et al, 2009;Wang et al, 2009). Although difficult to prove, the possibility of enhanced tumor progression should be taken into consideration.…”

A rapid and optimization-free procedure allows the in vivo detection of subtle cell cycle and ploidy alterations in tissues by flow cytometry

“…19 In these mice, SV40 T-Ag induces the development of mammary carcinoma associated with genomic instability and aneuploidy. 20 Histopathology of such specimens sometimes reveals a highly fresh tissue samples and examined prior to fixation, the majority of cells in the single cell suspension are still able to exclude trypan blue, indicating the integrity of the plasma membrane. However, it should be noted that the percentage of whole intact cells may vary significantly (~55-90%) depending on the tissue type.…”

“…19 H&E staining, pathology and tumor grading was carried out as described elsewhere. 20 All mice were housed and handled in accordance with official regulations for care and use of laboratory animals. For the irradiation experiments, mice were subjected to a whole-body radiation dose of 5 Gy using an open Cs 137 source.…”

Mechanism of Fatty Acid Synthase in Drug Tolerance Related to Epithelial-mesenchymal Transition of Breast Cancer

“…The cell cycle cannot be arrested in G1 phase if the p53 protein in tumour cells have mutated or are missing, thereby leading to drug tolerance because of a lack of apoptotic cells (Foster et al, 2012). Heinlein et al (2008) constructed p53 mutant mice, and found that p53 mutations induce breast cancer cell proliferation without affecting the stability of the genome. p53 can also induce tumour cell apoptosis by downregulating MSP/Mst1.…”