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Model Characteristics - Model:
Constitutive telomerase expression promotes mammary carcinomas in aging mice
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| Model Descriptor |
Constitutive telomerase expression promotes mammary carcinomas in aging mice
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| Official Nomenclature |
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| Genotype |
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| Species |
Mouse (Mus musculus)
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| Strain |
FVB/N
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| Is This a Tool Strain? |
No
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Developmental Stage
(applies only to Zebrafish) |
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| Experimental Design |
Telomerase is up-regulated in the vast majority of human cancers and serves to halt the progressive telomere shortening that ultimately blocks would-be cancer cells from achieving a full malignant phenotype. In contrast to humans, the laboratory mouse possesses long telomeres and, even in early generation telomerase-deficient mice, the level of telomere reserve is sufficient to avert telomere-based checkpoint responses and to permit full malignant progression. These features in the mouse provide an opportunity to determine whether enforced high-level telomerase activity can serve functions that extend beyond its ability to sustain telomere length and function. Here, we report the generation and characterization of transgenic mice that express the catalytic subunit of telomerase (mTERT) at high levels in a broad variety of tissues. br
Three founder lines (A, B, and C) were generated in which expression of the mTERT ORF was controlled by cis-regulatory elements that direct high-level transgene expression in most adult tissues. In the C line, the mTERT transgene segregated only with male mice, consistent with an integration event on the Y chromosome. To allow comparable analyses of both genders in the carcinogenesis experiments, most subsequent experiments were performed on founder lines A and B.
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| Phenotype |
Expression of mTERT conferred increased telomerase enzymatic activity in several tissues, including mammary gland, splenocytes, and cultured mouse embryonic fibroblasts. In mouse embryonic fibroblasts, mTERT overexpression extended telomere lengths but did not prevent culture-induced replicative arrest, thus reinforcing the view that this phenomenon is not related to occult telomere shortening. Robust telomerase activity, however, was associated with the spontaneous development of mammary intraepithelial neoplasia and invasive mammary carcinomas in a significant proportion of aged females. These data indicate that enforced mTERT expression can promote the development of spontaneous cancers even in the setting of ample telomere reserve.
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| Website for add. info |
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| Breeding Notes |
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| Sex Distribution of the Phenotype |
Both Sexes
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| Submitted by |
caMOD, Curator
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| Principal Investigator / Lab |
DePinho, Ronald
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| Comment |
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| Model Availability: This model is available from |
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