Haploid loss of Ki-ras delays mammary tumor progression in C3 (1)/SV40 Tag transgenic mice

Liu, Min‐Ling; Shibata, Masaaki; Lintig, Friederike C. von; Wang, Weili; Cassenaer, Stijn; Boss, Gerry R.; Green, Jeffrey E.

doi:10.1038/sj.onc.1204280

Cited by 14 publications

(13 citation statements)

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“…Kras2 amplification is associated with tumor progression in the C3(1)- Tag model [29], and haplo-insufficiency of Kras2 delays tumor progression [30]. High co-expression of Kras2 -linked genes prompted us to test whether DNA copy number changes might also account for the high expression of Kras2 among a subset of the human tumors.…”

Section: Resultsmentioning

confidence: 99%

Identification of conserved gene expression features between murine mammary carcinoma models and human breast tumors

et al. 2007

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(http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Breast cancer-model expression

Comparison of mammary tumor gene-expression profiles from thirteen murine models using microarrays and with that of human breast tumors showed that many of the defining characteristics of human subtypes were conserved among mouse models.

Abstract Background: Although numerous mouse models of breast carcinomas have been developed, we do not know the extent to which any faithfully represent clinically significant human phenotypes. To address this need, we characterized mammary tumor gene expression profiles from 13 different murine models using DNA microarrays and compared the resulting data to those from human breast tumors.

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Section: Resultsmentioning

confidence: 99%

Identification of conserved gene expression features between murine mammary carcinoma models and human breast tumors

et al. 2007

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“…This model is faithful to human BBC, which frequently features combined RB and p53 loss (32–36), and C3-TAg and human BBC show common patterns of gene expression by RNA expression profiling (24, 32). Of relevance to AZD/BEZ testing, tumors from this model frequently (∼30%), but not always, acquire K-Ras amplification with progression (37), and haploid loss of K-Ras delays progression in this model (38). Therefore, a fraction of tumors in this GEMM likely require persistent RAS activation for tumor maintenance, and we reasoned differential sensitivity to AZD/BEZ might correlate with K-Ras activation status.…”

Section: Resultsmentioning

confidence: 99%

Combined PI3K/mTOR and MEK Inhibition Provides Broad Antitumor Activity in Faithful Murine Cancer Models

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et al. 2012

Clinical Cancer Research

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Purpose Anticancer drug development is inefficient, but genetically engineered murine models (GEMM) and orthotopic, syngeneic transplants (OST) of cancer may offer advantages to in vitro and xenograft systems. Experimental Design We assessed the activity of 16 treatment regimens in a RAS-driven, Ink4a/Arf-deficient melanoma GEMM. In addition, we tested a subset of treatment regimens in three breast cancer models representing distinct breast cancer subtypes: claudin-low (T11 OST), basal-like (C3-TAg GEMM), and luminal B (MMTV-Neu GEMM). Results Like human RAS-mutant melanoma, the melanoma GEMM was refractory to chemotherapy and single-agent small molecule therapies. Combined treatment with AZD6244 [mitogen-activated protein–extracellular signal-regulated kinase kinase (MEK) inhibitor] and BEZ235 [dual phosphoinositide-3 kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitor] was the only treatment regimen to exhibit significant antitumor activity, showed by marked tumor regression and improved survival. Given the surprising activity of the "AZD/BEZ" combination in the melanoma GEMM, we next tested this regimen in the "claudin-low" breast cancer model that shares gene expression features with melanoma. The AZD/BEZ regimen also exhibited significant activity in this model, leading us to testing in even more diverse GEMMs of basal-like and luminal breast cancer. The AZD/BEZ combination was highly active in these distinct breast cancer models, showing equal or greater efficacy compared with any other regimen tested in studies of over 700 tumor-bearing mice. This regimen even exhibited activity in lapatinib-resistant HER2+ tumors. Conclusion These results show the use of credentialed murine models for large-scale efficacy testing of diverse anticancer regimens and predict that combinations of PI3K/mTOR and MEK inhibitors will show antitumor activity in a wide range of human malignancies.

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“…(22) The C3 1/ SV40 T-antigen transgenic mice of mammary cancer provided a useful model for studies on tumor development and apoptosis. (23,25,(45)(46)(47) These SV40Tag transgenic mice were generated in such a way that the transgene was under the control of a tissue-specific promoter. We have generated an inducible SV40Tag transgenic mouse model with a cytomegalovirus promoter.…”

Section: Discussionmentioning

confidence: 99%

Involvement of insulin‐like growth factor‐insulin receptor signal pathway in the transgenic mouse model of medulloblastoma

et al. 2008

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M edulloblastoma is an invasive embryonic tumor of the cerebellum with predominant neuronal differentiation. It is the most common malignant brain tumor of childhood, which mainly occurs between 5 and 10 years of age.(1) Despite recent advances in understanding the pathogenesis of medulloblastoma, the specific genetic alterations and molecular mechanisms involved in the brain tumor are not well defined.(2) It is generally accepted that medulloblastoma, like other cancers, represents a genetic disease of somatic cell alterations, such as gene mutations, deletions, translocations, or amplifications. The etiology and risk factors that contribute to the genetic aberrations for the tumors remain to be elucidated. It has been reported that aberrant activations of several cell signal pathways, such as Shh (3,4) Wnt (5,6) ErbB2 (7,8) and insulin-like growth factor 1-R (IGF1-R) pathways (9,10) were implicated in the pathological processes of brain tumors.Simian virus 40 (SV40) has been detected in medulloblastoma. (11,12) Several lines of evidence indicated that the viral early protein T antigen could be involved in the tumorigenesis process. SV40 T antigen (SV40Tag) is a multifunctional regulatory protein that binds to the tumor suppressor genes, including p53 (13) and the retinoblastoma (Rb) family of proteins.Furthermore, the antigen could interact with insulin receptor substrate I (IRS-1), which plays a critical role in transforming R-cells. (15,16) It is known that the interactions between SV40 Tantigen (SV40Tag) and tumor suppressor proteins stimulate DNA duplication, facilitate cell proliferation and induce cell transformation. (17,18) However, the molecular mechanism of the SV40 induction of tumors is not completely clear.Transgenic technology has provided a way to determine whether a particular gene product could contribute to the neoplastic process.Furthermore, the transgenic animal models could be used for studies on tumor development, progression and therapeutic targets identification and evaluation. Recently, a number of SV40Tag transgenic animal models have been reported, in which the transgene was constitutively expressed. (19)(20)(21)(22)(23)(24) These animal models were used for the studies of neoplastic development, as well as the equilibrium between proliferation and cell death. (25)(26)(27) However, the constitutive expression of SV40Tag may affect the development of the animal and therefore, hamper the analysis of critical steps of tumorigenesis. In an attempt to circumvent these limitations, we generated inducible transgenic mice expressing SV40Tag under the control of tetracycline. In this report, we have described the generation and molecular characterization of the tetracyclineresponsive SV40Tag transgenic mouse model for medulloblastoma. Materials and MethodsGeneration of the inducible SV40Tag transgenic mice. A 2.5-kb fragment containing the SV40Tag gene from pBC-SV40Tag (28) was generated with Xho I digestion and cloned into the Sal I site of pTRE-2 DNA vector (pTRE-SV40Tag). Linearized pTRE-S...

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Haploid loss of Ki-ras delays mammary tumor progression in C3 (1)/SV40 Tag transgenic mice

Cited by 14 publications

References 21 publications

Identification of conserved gene expression features between murine mammary carcinoma models and human breast tumors

Identification of conserved gene expression features between murine mammary carcinoma models and human breast tumors

Combined PI3K/mTOR and MEK Inhibition Provides Broad Antitumor Activity in Faithful Murine Cancer Models

Involvement of insulin‐like growth factor‐insulin receptor signal pathway in the transgenic mouse model of medulloblastoma

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