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. Author manuscript; available in PMC: 2015 Oct 1.
Published in final edited form as: Cell. 2007 May 18;129(4):838. doi: 10.1016/j.cell.2007.05.013

SnapShot: Genetic Mouse Models of Cancer

Lars Zender 1, Johannes Zuber 1, Scott W Lowe 1
PMCID: PMC4591003  NIHMSID: NIHMS724748  PMID: 17512415
Gene Genetic Approach Primary Tumor Types Cooperativity Models Clinical Significance
p53 Tumor Suppressor Trp53 mouse germline knockout. Trp53−/− homozygous: 100% tumor penetrance at ~4.5 months. Typical tumors: T cell lymphoma (>60%); soft tissue sarcoma (~25%); osteosarcoma, brain tumors, teratoma (together <15%); carcinomas rarely observed. Trp53+/− heterozygous: 50% tumor penetrance at 17 months. Typical tumors: T cell lymphoma (~30%); soft tissue sarcoma (~30%); osteosarcoma (~30%); more carcinomas than Trp53−/− mice. Oncogenic cooperativity observed between Trp53−/− and other lesions such as Rb−/− or Eμ-Myc. Carcinogenesis induced by different genotoxic agents or irradiation is accelerated in Trp53-deficient mice. Mutations in TP53 found in more than 50% of all human tumors.
Trp53 point mutation knockin mice express Trp53 (R172H) or Trp53 (R270H) from the endogenous locus. Tumor spectra differ from germline Trp53 knockout mice with more carcinomas, B cell lymphomas, endothelial tumors. In mice, Trp53 (R172H) and Kras (G12D) cooperate to promote chromosomal instability and metastatic pancreatic ductal adenocarcinoma. Li-Fraumeni syndrome patients have TP53 point mutations rather than deletions, so knockin mice are better models of this disease.
Conditional Trp53 knockout mice carry loxP sites in introns 1 and 10 of the Trp53 locus. Homozygous mice are not tumor prone. When crossed with mice expressing Cre in the germline, wild-type Trp53 allele is excised and mice develop the same tumor spectrum as Trp53 germline knockout mice. These mice develop breast cancer when crossed with Brca2 conditional knockout mice and K14-Cre mice. When crossed with Rb1 loxP/loxP mice, small-cell lung cancer results after treatment with Adeno-Cre and deletion of the two tumor suppressor genes. Breast cancer is the second most frequent cause of death among US women. 1 in 27 women dies of breast cancer. Small-cell lung cancer accounts for ~20% of all lung cancers.
Ink4a/Arf Tumor Suppressors Ink4a/Arf germline knockout mice carry a deletion of exon 2/3 of the Ink4a/Arf (Cdkn2a) locus eliminating both p16 (Ink4a) and p19 (Arf). Homozygous mice develop sarcomas (50%) and B cell lymphomas (50%) by ~32 weeks. In heterozygous animals, tumors appear with lower penetrance and longer latency and uniformly demonstrate loss of the wild-type allele. Loss of Ink4a/Arf cooperates with oncogenes expressed from tissue-specific promotors, such as tyrosinase-Ras (melanomas) and Eμ-Myc (B cell lymphomas). EGFR, if delivered in a retrovirus to glia, induces formation of gliomas in Ink4a/Arf homo- and heterozygous mice. Inactivation of the INK4a/ARF locus is one of the most common lesions in various human tumors and can arise from homozygous deletions (14%), point mutations (5%), or promoter methylation (20%).
Arf germline knockout mice lack p19 (Arf) due to deletion of exon 1β but express normal p16 (Ink4a). 80% of homozygous mice develop sarcomas (43%), T cell lymphomas (29%), carcinomas (17%), and neurological tumors (11%) by ~38 weeks. Tumors in heterozygous mice are less frequent and are accompanied by loss of the wild-type allele. Like loss of Trp53, Arf deficiency accelerates tumorigenesis induced by various mitogenic oncogenes, implicating Arf as a crucial mediator of oncogene signaling and a component of a cellular failsafe mechanism that counters hyperproliferative signals.
Ink4a germline knockout mice lack p16 (Ink4a) but express p19 (Arf). ~25% of the homozygous mice develop tumors (mainly sarcomas and lymphomas) by ~44 weeks. Ink4a knockout mice are prone to chemically induced carcinogenesis. Recent studies have implicated p16 in stem cell aging.
Kras Oncogene Conditional Lox-STOP-Lox-Kras2 (G12D) mice (LSL-Kras) express an activating mutant Kras allele from its endogenous locus after Cre-mediated excision of a STOP cassette. Non-small-cell lung cancer (adenocarcinoma) produced by intranasal administration of Adeno-Cre. Trp53 loss or mutation strongly promotes progression of Kras(G12D)-induced lung adenocarcinomas, yielding invasive desmoplastic tumors that metastasize early and resemble advanced human lung adenocarcinomas. Adenocarcinoma is the second most common type of non-small-cell lung cancer (after squamous cell carcinoma) and has increasing incidence rates.
Pancreatic cancer produced by crossing with Pdx-1-Cre transgenic mice. Activated Kras and Ink4a/Arf deficiency cooperate to produce metastatic pancreatic ductal adenocarcinoma with similar genetics and histopathology to human pancreatic cancer. Pancreatic cancer is fourth leading cause of cancer death in US; there is no effective treatment. Mutations in KRAS in ~90% of pancreatic cancers.
Myeloproliferative Disease (MPD) produced by crossing with Mx1-Cre mice and pI-pC treatment. Acute myeloid leukemia (AML) is associated with activating lesions in RAS signaling networks in ~60% of cases. There are 12,000 new patients/year in the US, with only a 30% cure rate.
Pten Tumor Suppressor Pten germline knockout. Homozygosity for the null Pten mutation results in embryonic lethality (E9.5). Pten+/− mice develop multiple tumor types (breast, thyroid, endometrium, prostate, and T cell lymphoma). Breast carcinoma development is accelerated in Pten+/− × MMTV-Wnt1 mice, less so in MMTV-Wnt1 mice. Only Pten+/− × Cdkn1b−/− mice but not Pten+/− mice rapidly develop prostate carcinomas at complete penetrance. Pten haploinsufficiency enables tumorigenesis. The PTEN tumor suppressor is mutated in human carcinomas (e.g., breast, prostate, and endometrium) and in glioblastoma. Cowden disease patients have PTEN mutations and increased cancer risk.
Conditional Pten knockout mice (Cre-loxP system). Prostate-specific knockout of Pten by crossing with probasin-Cre (PB-Cre) mice leads to induction of senescence, which delays development of prostate cancer (median onset after 4–6 months). Senescence is bypassed in PB-Cre × Pten loxP/loxP × Trp53 loxP/loxP compound mutant mice leading to rapid tumor development after puberty. Prostate cancer is the second leading cause of cancer-related death in US males.
Myc Oncogene Eμ-Myc mice express Myc in the B cell lineage under control of the immunoglobulin heavy chain enhancer (Eμ). Mice develop Burkitt-like lymphoblastic B cell lymphoma, diffuse large B cell lymphoma, and plasmacytoma at 2–6 months of age. Oncogenic cooperativity with other lesions (e.g., overexpression of Bcl-2, loss of Arf or Trp53). This cooperativity establishes oncogene-induced apoptosis as a primary barrier against tumorigenesis and a determinant of response to treatment. Insertional mutagenesis screens using Mo-MLV in Eμ-Myc mice led to discovery of oncogenes such as Bmi1 and Pim1. B cell non-Hodgkin lymphoma, the most common form of lymphoma, affects ~300,000 patients in the US (40% die within 5 years). Understanding heterogeneity in treatment response is a challenge for improving lymphoma therapy.
Conditional tet-o-Myc mice harbor Myc under control of the tetracycline-responsive element (TRE). Various tumors generated by crossing tet-o-Myc mice with tissue-specific tet-transactivator (tTA or rtTA) mice: liver carcinoma(LAP-tTA mice); T cell lymphoma, acute myeloid leukemia, and sarcoma (EμSR-tTA); breast adenocarcinoma (MMTV-rtTA). Reversible expression of Myc boosts understanding of oncogene addiction (tumor regression after withdrawal of the causative oncogene) and tumor dormancy (blocking of causative oncogenes allows cancer cells to survive in a nonproliferative state). Hepatocellular carcinoma is the fifth most common cancer worldwide and the third leading cause of cancer death due to lack of treatment options.
RIP1-Tag The RIP1-Tag transgene directs expression of SV40 T antigen (Tag) in β cells of the endocrine pancreas. Sequential development of hyperplasia, angiogenic hyperplasia, adenomas, and invasive carcinomas of pancreatic islets. Complete early penetrance plus multifocal disease enable detailed characterization of the different stages of tumor development and the role of angiogenesis. The model is widely used for preclinical drug testing.
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Genetically defined mouse models of human cancer provide a tractable experimental system for studying cancer genetics, pathology, and therapy in a physiological environment. For this SnapShot, we have selected mouse models of human cancers according to whether the models have made major contributions to understanding the function of a particular cancer gene or mechanisms of tumorigenesis (e.g., tumor suppressor p53 knockout mice and RIP-Tag mice). Whenever possible, we discuss models that accurately resemble major clinical tumor types. For more information about available models visit the website of the Mouse Models of Human Cancers Consortium (MMHCC, http://emice.nci.nih.gov).

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