Constitutive telomerase expression promotes mammary carcinomas in aging mice

Abstract

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. 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.

Telomerase stimulates ribosomal DNA transcription under hyperproliferative conditions

“…Recent data support the emerging idea that hTERT/telomerase possesses pro-tumorigenic activities that extend beyond its classical role in telomere elongation. Interestingly, in mouse tumours originating from telomerasepositive tissues, an increase in telomerase activity has been observed, and overexpression of telomerase supports tumour formation in mouse tissues with long telomeres, indicating that telomerase has functions in tumorigenesis that are independent of telomere lengthening 1,[26][27][28] .…”

TRF2 inhibition promotes anchorage-independent growth of telomerase-positive human fibroblasts

“…Both in vitro and in vivo, overexpression of telomerase in cancer cells appears to be crucial for tumor progression (Greenberg et al, 1999;Hahn et al, 1999a, b;Gonzalez-Suarez et al, 2000Elenbaas et al, 2001;Artandi et al, 2002). On the other hand, studies on mice lacking the telomerase RNA gene demonstrate that critical telomere shortening and telomere instability can favor initial stages of cancer formation and cooperates with p53 deficiency to favor carcinogenesis Rudolph et al, 2001).…”

Are aneuploidy and chromosome breakage caused by a CINgle mechanism?

“…Over the last few years, it has become clear that telomere shortening is probably a minor factor in the initiation of genomic instability, although telomerase reactivation probably plays an important role in tumor progression. 28 DNA repair defects 29 or fragile sites 30 have alternatively been suggested to initiate genetic instability. In contrast to a proposed repair defect, many CIN tumors show upregulation of DSB repair pathways such as non-homologous end joining.…”