Rats Deficient for P53 Are Susceptible to Spontaneous and Carcinogen-induced Tumorigenesis

Overview

Journal Carcinogenesis

Specialty Oncology

Date 2012 Jul 14

PMID 22791818

Citations 13

Authors

He-Xin Yan

Hong-Ping Wu

Charles Ashton

Chang Tong

Qi-Long Ying

Affiliations

Soon will be listed here.

Abstract

The p53 tumor suppressor gene is highly mutated in human cancers. Individuals who inherit one p53 mutant allele are susceptible to a wide range of tumor types, including breast cancer and sarcoma. We recently generated p53 knockout rats through gene targeting in embryonic stem cells. Here we show that rats homozygous for the null allele are prone to early onset spontaneous sarcomas and lymphoma with high incidence of metastases. Heterozygous rats are also highly predisposed to cancer, but with a delayed onset and a wider spectrum of tumor types compared with homozygotes. Importantly, up to 20% of female heterozygotes developed breast cancer and about 70% of the tumors were positive for estrogen receptor. Exposing p53-deficient rats to a low dose of the carcinogen diethylnitrosamine dramatically decreased the latency for sarcoma development and survival time compared with equivalently treated wild-type rats. These unique features make this knockout line a valuable model for investigating human malignancy and in vivo carcinogenicity of chemicals and therapeutic compounds.

Citing Articles

Rat Models of Breast Cancer.

Bu W, Li Y Adv Exp Med Biol. 2025; 1464():123-148.

PMID: 39821024 DOI: 10.1007/978-3-031-70875-6_8.

TP53 in Biology and Treatment of Osteosarcoma.

Synoradzki K, Bartnik E, Czarnecka A, Fiedorowicz M, Firlej W, Brodziak A Cancers (Basel). 2021; 13(17).

PMID: 34503094 PMC: 8428337. DOI: 10.3390/cancers13174284.

Genetic modifiers regulating DNA replication and double-strand break repair are associated with differences in mammary tumors in mouse models of Li-Fraumeni syndrome.

Majhi P, Griner N, Mayfield J, Compton S, Kane J, Baptiste T Oncogene. 2021; 40(31):5026-5037.

PMID: 34183771 PMC: 8349885. DOI: 10.1038/s41388-021-01892-5.

Rat models of human diseases and related phenotypes: a systematic inventory of the causative genes.

Szpirer C J Biomed Sci. 2020; 27(1):84.

PMID: 32741357 PMC: 7395987. DOI: 10.1186/s12929-020-00673-8.

TP53-Deficient Angiosarcoma Expression Profiling in Rat Model.

Smyczynska U, Strzemecki D, Czarnecka A, Fendler W, Fiedorowicz M, Welniak-Kaminska M Cancers (Basel). 2020; 12(6).

PMID: 32532104 PMC: 7352674. DOI: 10.3390/cancers12061525.

References

Wienholds E, van Eeden F, Kosters M, Mudde J, Plasterk R, Cuppen E . Efficient target-selected mutagenesis in zebrafish. Genome Res. 2003; 13(12):2700-7. PMC: 403812. DOI: 10.1101/gr.1725103. View

Tong C, Li P, Wu N, Yan Y, Ying Q . Production of p53 gene knockout rats by homologous recombination in embryonic stem cells. Nature. 2010; 467(7312):211-3. PMC: 2937076. DOI: 10.1038/nature09368. View

Izsvak Z, Frohlich J, Grabundzija I, Shirley J, Powell H, Chapman K . Generating knockout rats by transposon mutagenesis in spermatogonial stem cells. Nat Methods. 2010; 7(6):443-5. PMC: 2886193. DOI: 10.1038/nmeth.1461. View

Cotroneo M, Haag J, Zan Y, Lopez C, Thuwajit P, Petukhova G . Characterizing a rat Brca2 knockout model. Oncogene. 2006; 26(11):1626-35. DOI: 10.1038/sj.onc.1209960. View

Amos-Landgraf J, Kwong L, Kendziorski C, Reichelderfer M, Torrealba J, Weichert J . A target-selected Apc-mutant rat kindred enhances the modeling of familial human colon cancer. Proc Natl Acad Sci U S A. 2007; 104(10):4036-41. PMC: 1805486. DOI: 10.1073/pnas.0611690104. View

Krug U, Ganser A, Koeffler H . Tumor suppressor genes in normal and malignant hematopoiesis. Oncogene. 2002; 21(21):3475-95. DOI: 10.1038/sj.onc.1205322. View

Chen Y, Yee D, Dains K, Chatterjee A, Cavalcoli J, Schneider E . Genotype-based screen for ENU-induced mutations in mouse embryonic stem cells. Nat Genet. 2000; 24(3):314-7. DOI: 10.1038/73557. View

Olivier M, Hollstein M, Hainaut P . TP53 mutations in human cancers: origins, consequences, and clinical use. Cold Spring Harb Perspect Biol. 2010; 2(1):a001008. PMC: 2827900. DOI: 10.1101/cshperspect.a001008. View

Hollstein M, Sidransky D, Vogelstein B, Harris C . p53 mutations in human cancers. Science. 1991; 253(5015):49-53. DOI: 10.1126/science.1905840. View

10.

Donehower L, Lozano G . 20 years studying p53 functions in genetically engineered mice. Nat Rev Cancer. 2009; 9(11):831-41. DOI: 10.1038/nrc2731. View

11.

Kuperwasser C, Hurlbut G, Kittrell F, Dickinson E, Laucirica R, Medina D . Development of spontaneous mammary tumors in BALB/c p53 heterozygous mice. A model for Li-Fraumeni syndrome. Am J Pathol. 2000; 157(6):2151-9. PMC: 1885755. DOI: 10.1016/S0002-9440(10)64853-5. View

12.

Jacks T, Remington L, Williams B, Schmitt E, Halachmi S, Bronson R . Tumor spectrum analysis in p53-mutant mice. Curr Biol. 1994; 4(1):1-7. DOI: 10.1016/s0960-9822(00)00002-6. View

13.

Abbott A . Laboratory animals: the Renaissance rat. Nature. 2004; 428(6982):464-6. DOI: 10.1038/428464a. View

14.

Malkin D, Li F, Strong L, Fraumeni Jr J, Nelson C, Kim D . Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science. 1990; 250(4985):1233-8. DOI: 10.1126/science.1978757. View

15.

Donehower L, Harvey M, Slagle B, McArthur M, Montgomery Jr C, Butel J . Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature. 1992; 356(6366):215-21. DOI: 10.1038/356215a0. View

16.

Ikezaki S, Takagi M, Tamura K . Natural occurrence of neoplastic lesions in young sprague-dawley rats. J Toxicol Pathol. 2012; 24(1):37-40. PMC: 3234627. DOI: 10.1293/tox.24.37. View

17.

Dinse G, Peddada S, Harris S, Elmore S . Comparison of NTP historical control tumor incidence rates in female Harlan Sprague Dawley and Fischer 344/N Rats. Toxicol Pathol. 2010; 38(5):765-75. PMC: 4791045. DOI: 10.1177/0192623310373777. View

18.

Harvey M, McArthur M, Montgomery Jr C, Butel J, Bradley A, Donehower L . Spontaneous and carcinogen-induced tumorigenesis in p53-deficient mice. Nat Genet. 1993; 5(3):225-9. DOI: 10.1038/ng1193-225. View

19.

Son W, Bell D, Taylor I, Mowat V . Profile of early occurring spontaneous tumors in Han Wistar rats. Toxicol Pathol. 2010; 38(2):292-6. DOI: 10.1177/0192623309359794. View

20.

van Boxtel R, Kuiper R, Toonen P, van Heesch S, Hermsen R, de Bruin A . Homozygous and heterozygous p53 knockout rats develop metastasizing sarcomas with high frequency. Am J Pathol. 2011; 179(4):1616-22. PMC: 3181367. DOI: 10.1016/j.ajpath.2011.06.036. View