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ABSTRACT: MYC and phosphoinositide 3-kinase (PI3K)-pathway deregulation are common in human prostate cancer. Through examination of 194 human prostate tumors, we observed statistically significant co-occurrence of MYC amplification and PI3K-pathway alteration, raising the possibility that these two lesions cooperate in prostate cancer progression. To investigate this, we generated bigenic mice in which both activated human AKT1 and human MYC are expressed in the prostate (MPAKT/Hi-MYC model). In contrast to mice expressing AKT1 alone (MPAKT model) or MYC alone (Hi-MYC model), the bigenic phenotype demonstrates accelerated progression of mouse prostate intraepithelial neoplasia (mPIN) to microinvasive disease with disruption of basement membrane, significant stromal remodeling and infiltration of macrophages, B- and T-lymphocytes, similar to inflammation observed in human prostate tumors. In contrast to the reversibility of mPIN lesions in young MPAKT mice after treatment with mTOR inhibitors, Hi-MYC and bigenic MPAKT/Hi-MYC mice were resistant. Additionally, older MPAKT mice showed reduced sensitivity to mTOR inhibition, suggesting that additional genetic events may dampen mTOR dependence. Since increased MYC expression is an early feature of many human prostate cancers, these data have implications for treatment of human prostate cancers with PI3K-pathway alterations using mTOR inhibitors.
PLoS ONE 01/2011; 6(3):e17449. · 4.09 Impact Factor
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Jennifer C King,
Jin Xu,
John Wongvipat,
Haley Hieronymus,
Brett S Carver,
David H Leung,
Barry S Taylor,
Chris Sander,
Robert D Cardiff, Suzana S Couto,
William L Gerald,
Charles L Sawyers
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ABSTRACT: The TMPRSS2-ERG fusion, present in approximately 50% of prostate cancers, is less common in prostatic intraepithelial neoplasia (PIN), raising questions about whether TMPRSS2-ERG contributes to disease initiation. We identified the translational start site of a common TMPRSS2-ERG fusion and showed that transgenic TMPRSS2-ERG mice develop PIN, but only in the context of PI3-kinase pathway activation. TMPRSS2-ERG-positive human tumors are also enriched for PTEN loss, suggesting cooperation in prostate tumorigenesis.
Nature Genetics 06/2009; 41(5):524-6. · 35.53 Impact Factor
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ABSTRACT: Tumor suppressor gene PTEN is important in the initiation and progression of human prostate carcinoma, whereas the role of TP53 remains controversial. Since Pten/Trp53 double conditional knockout mice show earlier onset and fast progression of prostate cancer when compared to Pten knockout mice, we asked whether heterozygosity of these two tumor suppressor genes was sufficient to accelerate prostatic tumorigenesis. To answer this question we examined prostatic lesion progression of Pten/Trp53 double heterozygous mice and a series of controls such as Pten heterozygous, Pten conditional knockout, Trp53 heterozygous and Trp53 knockout mice. Tissue recombination of adult prostatic epithelium coupled with embryonic rat seminal vesicle mesenchyme was used as a tool to stimulate prostatic epithelial proliferation. In our study, high-grade prostatic intraepithelial neoplasia (PIN) was found with high frequency at 8 weeks post-tissue recombination transplantation. PIN lesions in Pten/Trp53 double heterozygous mice were more severe than those seen in Pten heterozygous alone. Furthermore, morphologic features attributable to Pten or Trp53 loss appeared to be enhanced in double heterozygous tissues. LOH analysis of Pten and Trp53 in genomic DNA collected from high-grade PIN lesions in Pten heterozygous and Pten/Trp53 double heterozygous mice showed an intact wild-type allele for both genes in all samples examined. In conclusion, simultaneous heterozygosity of Pten and Trp53 accelerates prostatic tumorigenesis in this mouse model of prostate cancer independently of loss of heterozygosity of either gene.
Differentiation 02/2009; 77(1):103-11. · 2.81 Impact Factor
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ABSTRACT: The Mre11 complex (Mre11, Rad50, and Nbs1) and Chk2 have been implicated in the DNA-damage response, an inducible process required for the suppression of malignancy. The Mre11 complex is predominantly required for repair and checkpoint activation in S phase, whereas Chk2 governs apoptosis. We examined the relationship between the Mre11 complex and Chk2 in the DNA-damage response via the establishment of Nbs1(DeltaB/DeltaB) Chk2(-/-) and Mre11(ATLD1/ATLD1) Chk2(-/-) mice. Chk2 deficiency did not modify the checkpoint defects or chromosomal instability of Mre11 complex mutants; however, the double-mutant mice exhibited synergistic defects in DNA-damage-induced p53 regulation and apoptosis. Nbs1(DeltaB/DeltaB) Chk2(-/-) and Mre11(ATLD1/ATLD1) Chk2(-/-) mice were also predisposed to tumors. In contrast, DNA-PKcs-deficient mice, in which G1-specific chromosome breaks are present, did not exhibit synergy with Chk2(-/-) mutants. These data suggest that Chk2 suppresses the oncogenic potential of DNA damage arising during S and G2 phases of the cell cycle.
Molecular cell 08/2008; 31(1):21-32. · 14.61 Impact Factor
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ABSTRACT: Dyskeratosis congenita (DC) is an inherited bone marrow failure syndrome characterized by cutaneous symptoms, including hyperpigmentation and nail dystrophy. Some forms of DC are caused by mutations in telomerase, the enzyme that counteracts telomere shortening, suggesting a telomere-based disease mechanism. However, mice with extensively shortened telomeres due to telomerase deficiency do not develop the characteristics of DC, raising questions about the etiology of DC and/or mouse models for human telomere dysfunction. Here we describe mice engineered to undergo telomere degradation due to the absence of the shelterin component POT1b. When combined with reduced telomerase activity, POT1b deficiency elicits several characteristics of DC, including hyperpigmentation and fatal bone marrow failure at 4-5 mo of age. These results provide experimental support for the notion that DC is caused by telomere dysfunction, and demonstrate that key aspects of a human telomere-based disease can be modeled in the mouse.
Genes & Development 08/2008; 22(13):1773-85. · 11.66 Impact Factor
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ABSTRACT: The transgenic adenocarcinoma of mouse prostate (TRAMP) model is widely used in prostate cancer research because of rapid tumor onset and progression. The transgenic mouse is on a C57BL/6 (B6) background and expresses SV40 T-antigen under the probasin promoter. The strong genetic component of susceptibility to prostate cancer in humans prompted us to investigate the effect of mouse strain background (FVB and B6) on incidence, progression, and pathology of prostate cancer in this model. Because TRAMP lesions are unique but differ from conventional prostatic intraepithelial neoplasia because the epithelium and stroma are affected diffusely, we designated them as "atypical hyperplasia of Tag." Although the incidence and severity of atypical hyperplasia of Tag is similar, FVB-TRAMP mice live significantly shorter lives than B6-TRAMP mice because of the rapid development and progression of neuroendocrine carcinomas. This is associated with an increased frequency of neuroendocrine precursor lesions in young TRAMP mice, detectable at 4 weeks after birth. These lesions show properties of bipotential stem cells and co-express markers of epithelial (E-cadherin) and neuroendocrine (synaptophysin) lineages, as well as the transcription factors Foxa1 and Foxa2. Transplantation studies using TRAMP prostatic ducts suggested that neuroendocrine carcinomas arise independently from atypical hyperplasias or other epithelial lesions. Adenocarcinomas were not seen in our cohort. Thus, neuroendocrine carcinomas are the principal malignancy in this model and may develop from bipotential progenitor cells at an early stage of prostate tumorigenesis.
American Journal Of Pathology 02/2008; 172(1):236-46. · 4.89 Impact Factor
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ABSTRACT: The MRE11 complex (MRE11, RAD50 and NBS1) and the ataxia-telangiectasia mutated (ATM) kinase function in the same DNA damage response pathway to effect cell cycle checkpoint activation and apoptosis. The functional interaction between the MRE11 complex and ATM has been proposed to require a conserved C-terminal domain of NBS1 for recruitment of ATM to sites of DNA damage. Human Nijmegen breakage syndrome (NBS) cells and those derived from multiple mouse models of NBS express a hypomorphic NBS1 allele that exhibits impaired ATM activity despite having an intact C-terminal domain. This indicates that the NBS1 C terminus is not sufficient for ATM function. We derived Nbs1(DeltaC/DeltaC) mice in which the C-terminal ATM interaction domain is deleted. Nbs1(DeltaC/DeltaC) cells exhibit intra-S-phase checkpoint defects, but are otherwise indistinguishable from wild-type cells with respect to other checkpoint functions, ionizing radiation sensitivity and chromosome stability. However, multiple tissues of Nbs1(DeltaC/DeltaC) mice showed a severe apoptotic defect, comparable to that of ATM- or CHK2-deficient animals. Analysis of p53 transcriptional targets and ATM substrates showed that, in contrast to the phenotype of Chk2(-/-) mice, NBS1(DeltaC) does not impair the induction of proapoptotic genes. Instead, the defects observed in Nbs1(DeltaC/DeltaC) result from impaired phosphorylation of ATM targets including SMC1 and the proapoptotic factor, BID.
Nature 05/2007; 447(7141):218-21. · 36.28 Impact Factor
