Modeling human lung cancer in mice: similarities and shortcomings

Tuveson, David A.; Jacks, Tyler

doi:10.1038/sj.onc.1203107

Cited by 123 publications

(95 citation statements)

References 77 publications

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“…To determine if BRM loss in vivo can contribute to cancer development, we utilized the ethyl carbamate mouse model, which has been described previously (Tuveson and Jacks, 1999). We bred heterozygous BRM mice to generate wild-type, heterozygous or null BRM mice (Figure 5a).…”

Section: Loss Of Brm Expression Potentiated Tumor Developmentmentioning

confidence: 99%

The reversible epigenetic silencing of BRM: implications for clinical targeted therapy

et al. 2007

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The SWI/SNF chromatin-remodeling complex serves as a master switch that directs and limits the execution of specific cellular programs, such as differentiation and growth control. SWI/SNF function requires one of two paralogous ATPase subunits, Brahma (BRM) or BRMrelated gene 1 (BRG1), which we previously found are lost together in cancer cell lines and primary lung cancers. Although BRG1 has been found to be mutated in cancer cell lines, the mechanisms underlying BRM silencing are not known. To address this question, we sequenced BRM in 10 BRM/BRG1-deficient cancer cell lines and found that BRM was devoid of abrogating mutations. Moreover, histone deacetylase (HDAC) inhibitors restored BRM expression in each of these BRG1/BRM-deficient cancer cell lines, indicating that epigenetic silencing is a major mechanism underlying the loss of BRM expression. Despite their ability to restore BRM expression, these HDAC inhibitors also blocked BRM function when present. However, after their removal, we observed that BRM expression remained elevated for several days, and during this period, BRM activity was detected. We also found that the suppression of BRM occurs in a broad range of human tumor types and that loss of one or both BRM alleles potentiated tumor development in mice. Thus, BRG1 and BRM are silenced by different mechanisms, and it may be possible to clinically target and reexpress BRM in a number of tumor types, potentially impacting tumor development.

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Section: Loss Of Brm Expression Potentiated Tumor Developmentmentioning

confidence: 99%

The reversible epigenetic silencing of BRM: implications for clinical targeted therapy

et al. 2007

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“…Patients are usually diagnosed with lung cancer because of disease symptoms or incidental chest Xray findings. Perhaps owing to the inability to recognize premalignant lesions, patients are seldom diagnosed before their cancer has reached an advanced stage (Tuveson and Jacks 1999).…”

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confidence: 99%

Analysis of lung tumor initiation and progression using conditional expression of oncogenic K-ras

Jackson¹,

Willis²,

Mercer³

et al. 2001

Genes Dev.

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1,770

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Adenocarcinoma of the lung is the most common form of lung cancer, but the cell of origin and the stages of progression of this tumor type are not well understood. We have developed a new model of lung adenocarcinoma in mice harboring a conditionally activatable allele of oncogenic K-ras. Here we show that the use of a recombinant adenovirus expressing Cre recombinase (AdenoCre) to induce K-ras G12D expression in the lungs of mice allows control of the timing and multiplicity of tumor initiation. Through the ability to synchronize tumor initiation in these mice, we have been able to characterize the stages of tumor progression. Of particular significance, this system has led to the identification of a new cell type contributing to the development of pulmonary adenocarcinoma.

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“…There have been very few spontaneous lung tumor mouse models available until now (37) and, in particular, no appropriate animal model for the study of oxidative DNA damage and lung tumorigenesis. These mouse models will facilitate tumorigenesis studies with regard to evaluating the contribution of oxidative stress and carcinogens and the efficacy of prevention and treatment strategies.…”

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confidence: 99%

Deficiencies in Mouse Myh and Ogg1 Result in Tumor Predisposition and G to T Mutations in Codon 12 of the K-Ras Oncogene in Lung Tumors

et al. 2004

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Oxidative DNA damage is unavoidably and continuously generated by oxidant byproducts of normal cellular metabolism. The DNA damage repair genes, mutY and mutM, prevent G to T mutations caused by reactive oxygen species in Escherichia coli, but it has remained debatable whether deficiencies in their mammalian counterparts, Myh and Ogg1, are directly involved in tumorigenesis. Here, we demonstrate that deficiencies in Myh and Ogg1 predispose 65.7% of mice to tumors, predominantly lung and ovarian tumors, and lymphomas. Remarkably, subsequent analyses identified G to T mutations in 75% of the lung tumors at an activating hot spot, codon 12, of the K-ras oncogene, but none in their adjacent normal tissues. Moreover, malignant lung tumors were increased with combined heterozygosity of Msh2, a mismatch repair gene involved in oxidative DNA damage repair as well. Thus, oxidative DNA damage appears to play a causal role in tumorigenesis, and codon 12 of K-ras is likely to be an important downstream target in lung tumorigenesis. The multiple oxidative repair genes are required to prevent mutagenesis and tumor formation. The mice described here provide a valuable model for studying the mechanisms of oxidative DNA damage in tumorigenesis and investigating preventive or therapeutic approaches.

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Modeling human lung cancer in mice: similarities and shortcomings

Cited by 123 publications

References 77 publications

The reversible epigenetic silencing of BRM: implications for clinical targeted therapy

The reversible epigenetic silencing of BRM: implications for clinical targeted therapy

Analysis of lung tumor initiation and progression using conditional expression of oncogenic K-ras

Deficiencies in Mouse Myh and Ogg1 Result in Tumor Predisposition and G to T Mutations in Codon 12 of the K-Ras Oncogene in Lung Tumors

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