Constitutive telomerase expression promotes mammary carcinomas in aging mice.
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.
Artandi
Steven E
SE
Department of Adult Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street (M413), Boston, MA 02115, USA.
Alson
Scott
S
Tietze
Maja K
MK
Sharpless
Norman E
NE
Ye
Siqin
S
Greenberg
Roger A
RA
Castrillon
Diego H
DH
Horner
James W
JW
Weiler
Sarah R
SR
Carrasco
Ruben D
RD
DePinho
Ronald A
RA
D015127:9,10-Dimethyl-1,2-benzanthracene; D000375:Aging; D000818:Animals; D020134:Catalytic Domain; D003001:Cloning, Molecular; D004268:DNA-Binding Proteins; D005260:Female; D015870:Gene Expression; D007700:Kinetics; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016366:Open Reading Frames; D019098:Telomerase / Q000235:genetics*; D016615:Telomere / Q000235:genetics
D004268:DNA-Binding Proteins; D015127:9,10-Dimethyl-1,2-benzanthracene; D019098:Telomerase