@article {240, title = {The Trp53 delta proline (Trp53ΔP) mouse exhibits increased genome instability and susceptibility to radiation-induced, but not spontaneous, tumor development.}, journal = {Mol Carcinog}, volume = {55}, year = {2016}, month = {2016 Sep}, pages = {1387-96}, abstract = {

The tumor suppressor TP53 can initiate a plethora of anti-proliferative effects to maintain genomic integrity under conditions of genotoxic stress. The N-terminal proline-rich domain (PRD) of TP53 is important in the regulation of TP53 activity and stability. A common polymorphism at codon 72 in this region has been associated with altered cancer risk in humans. The Trp53ΔP mouse, which carries a germline homozygous deletion of a region of the PRD, does not develop spontaneous tumors in a mixed 129/Sv and C57BL/6 genetic background, but is highly susceptible to a broad range of tumor types following total body exposure to 4 Gy gamma (γ) radiation. This contrasts with the tumor spectrum in Trp53 null (-/-) mice, which mainly develop thymic lymphomas and osteosarcomas. Analysis of genomic instability in tissues and cells from Trp53ΔP mice demonstrated elevated basal levels of aneuploidy, but this is not sufficient to drive spontaneous tumorigenesis, which requires an additional DNA damage stimulus. Levels of genomic instability did not increase significantly in Trp53ΔP mice following irradiation exposure, suggesting that other radiation effects including tissue inflammation, altered metabolism or autophagy, may play an important role. The Trp53ΔP mouse is a novel model to dissect the mechanisms of tumor development induced by radiation exposure. {\textcopyright} 2015 Wiley Periodicals, Inc.

}, issn = {1098-2744}, doi = {10.1002/mc.22377}, author = {Adams, Cassandra J and Yu, Jennifer S and Jiang-Hua Mao and Jen, Kuang-Yu and Costes, Sylvain V and Wade, Mark and Shoemake, Jocelyn and Aina, Olulanu H and Del Rosario, Reyno and Menchavez, Phuong Thuy and Cardiff, Robert D and Wahl, Geoffrey M and Balmain, Allan} } @article {200, title = {Ptch1 overexpression drives skin carcinogenesis and developmental defects in K14Ptch(FVB) mice.}, journal = {J Invest Dermatol}, volume = {133}, year = {2013}, month = {2013 May}, pages = {1311-20}, abstract = {

Ptch1 is a key regulator of embryonic development, acting through the sonic hedgehog (SHH) signaling pathway. Ptch1 is best known as a tumor suppressor, as germline or somatic mutations in Ptch1 lead to the formation of skin basal cell carcinomas. Here we show that Ptch1 also acts as a lineage-dependent oncogene, as overexpression of Ptch1 in adult skin in K14Ptch(FVB) transgenic mice synergizes with chemically induced Hras mutations to promote squamous carcinoma development. These effects were not because of aberrant activation of SHH signaling by the K14Ptch(FVB) transgene, as developmental defects in the highest expressing transgenic lines were consistent with the inhibition of this pathway. Carcinomas from K14Ptch(FVB) transgenic mice had only a small number of nonproliferative Ptch1 transgene-positive cells, suggesting that the Ptch1 transgene is not required for tumor maintenance, but may have a critical role in cell-fate determination at the initiation stage.

}, keywords = {9,10-Dimethyl-1,2-benzanthracene, Animals, Carcinoma, Squamous Cell, Disease Models, Animal, Fetal Development, Gene Expression Regulation, Neoplastic, Hedgehog Proteins, Keratin-14, Mice, Mice, Inbred C57BL, Mice, Transgenic, Mutation, Proto-Oncogene Proteins p21(ras), Receptors, Cell Surface, Signal Transduction, Skin Neoplasms, Transgenes}, issn = {1523-1747}, doi = {10.1038/jid.2012.419}, author = {Kang, Hio Chung and Wakabayashi, Yuichi and Jen, Kuang-Yu and Jiang-Hua Mao and Zoumpourlis, Vassilis and Del Rosario, Reyno and Balmain, Allan} } @article {179, title = {Progressive genomic instability in the FVB/Kras(LA2) mouse model of lung cancer.}, journal = {Mol Cancer Res}, volume = {9}, year = {2011}, month = {2011 Oct}, pages = {1339-45}, abstract = {

Alterations in DNA copy number contribute to the development and progression of cancers and are common in epithelial tumors. We have used array Comparative Genomic Hybridization (aCGH) to visualize DNA copy number alterations across the genomes of lung tumors in the Kras(LA2) model of lung cancer. Copy number gain involving the Kras locus, as focal amplification or whole chromosome gain, is the most common alteration in these tumors and with a prevalence that increased significantly with increasing tumor size. Furthermore, Kras amplification was the only major genomic event among the smallest lung tumors, suggesting that this alteration occurs early during the development of mutant Kras-driven lung cancers. Recurring gains and deletions of other chromosomes occur progressively more frequently among larger tumors. These results are in contrast to a previous aCGH analysis of lung tumors from Kras(LA2) mice on a mixed genetic background, in which relatively few DNA copy number alterations were observed regardless of tumor size. Our model features the Kras(LA2) allele on the inbred FVB/N mouse strain, and in this genetic background, there is a highly statistically significant increase in level of genomic instability with increasing tumor size. These data suggest that recurring DNA copy alterations are important for tumor progression in the Kras(LA2) model of lung cancer and that the requirement for these alterations may be dependent on the genetic background of the mouse strain.

}, keywords = {Animals, Cell Line, Tumor, Chromosome Aberrations, Disease Models, Animal, Disease Progression, DNA Copy Number Variations, DNA, Neoplasm, Gene Dosage, Gene Expression Regulation, Neoplastic, Genes, ras, Genomic Instability, Lung Neoplasms, Mice, Mice, Inbred C57BL, Proto-Oncogene Proteins p21(ras)}, issn = {1557-3125}, doi = {10.1158/1541-7786.MCR-11-0219}, author = {To, Minh D and Quigley, David A and Jiang-Hua Mao and Del Rosario, Reyno and Hsu, Jeff and Hodgson, Graeme and Jacks, Tyler and Balmain, Allan} } @article {143, title = {Mutually exclusive mutations of the Pten and ras pathways in skin tumor progression.}, journal = {Genes Dev}, volume = {18}, year = {2004}, month = {2004 Aug 1}, pages = {1800-5}, abstract = {

Pten heterozygous (Pten+/-) mice develop increased papilloma numbers and show decreased carcinoma latency time in comparison with controls after skin treatment with dimethyl benzanthracene (DMBA) and tetradecanoyl-phorbol acetate (TPA). H-ras mutation is normally a hallmark of DMBA-TPA-induced skin tumors, but 70\% of carcinomas from Pten+/- mice do not exhibit this mutation, and in all cases have lost the wild-type Pten allele. Tumors that retain the Pten wild-type allele also have H-ras mutations, indicating that activation of H-ras and complete loss of Pten are mutually exclusive events in skin carcinomas. Mitogen-activated protein kinase (MAPK) is consistently activated in the tumors with H-ras mutations, but is strongly down-regulated in Pten-/- tumors, suggesting that this pathway is dispensable for skin carcinoma formation. These data have important implications in designing individual therapeutic strategies for the treatment of cancer.

}, keywords = {9,10-Dimethyl-1,2-benzanthracene, Animals, Disease Progression, Genes, ras, Heterozygote, Homozygote, Loss of Heterozygosity, Mice, Mice, Inbred C57BL, Mice, Knockout, Mitogen-Activated Protein Kinases, Mutation, Papilloma, Protein Tyrosine Phosphatases, PTEN Phosphohydrolase, Signal Transduction, Skin Neoplasms, Tetradecanoylphorbol Acetate, Tumor Suppressor Proteins}, issn = {0890-9369}, doi = {10.1101/gad.1213804}, author = {Jiang-Hua Mao and To, Minh D and Perez-Losada, Jesus and Wu, Di and Del Rosario, Reyno and Balmain, Allan} }