Constitutive telomerase expression promotes mammary carcinomas in aging mice

Steven E. Artandi, Scott Alson, Maja K. Tietze, Norman E. Sharpless, Siqin Ye, Roger A. Greenberg, Diego H. Castrillon, James W. Horner, Sarah R. Weiler, Ruben D. Carrasco, Ronald A. DePinho

Research output: Contribution to journalArticle

240 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)8191-8196
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume99
Issue number12
DOIs
StatePublished - Jun 11 2002

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Telomerase
Telomere
Breast Neoplasms
Telomere Shortening
Neoplasms
Fibroblasts
Human Mammary Glands
Transgenic Mice
Breast
Phenotype

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Artandi, S. E., Alson, S., Tietze, M. K., Sharpless, N. E., Ye, S., Greenberg, R. A., ... DePinho, R. A. (2002). Constitutive telomerase expression promotes mammary carcinomas in aging mice. Proceedings of the National Academy of Sciences of the United States of America, 99(12), 8191-8196. https://doi.org/10.1073/pnas.112515399

Constitutive telomerase expression promotes mammary carcinomas in aging mice. / Artandi, Steven E.; Alson, Scott; Tietze, Maja K.; Sharpless, Norman E.; Ye, Siqin; Greenberg, Roger A.; Castrillon, Diego H.; Horner, James W.; Weiler, Sarah R.; Carrasco, Ruben D.; DePinho, Ronald A.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 99, No. 12, 11.06.2002, p. 8191-8196.

Research output: Contribution to journalArticle

Artandi, SE, Alson, S, Tietze, MK, Sharpless, NE, Ye, S, Greenberg, RA, Castrillon, DH, Horner, JW, Weiler, SR, Carrasco, RD & DePinho, RA 2002, 'Constitutive telomerase expression promotes mammary carcinomas in aging mice', Proceedings of the National Academy of Sciences of the United States of America, vol. 99, no. 12, pp. 8191-8196. https://doi.org/10.1073/pnas.112515399
Artandi, Steven E. ; Alson, Scott ; Tietze, Maja K. ; Sharpless, Norman E. ; Ye, Siqin ; Greenberg, Roger A. ; Castrillon, Diego H. ; Horner, James W. ; Weiler, Sarah R. ; Carrasco, Ruben D. ; DePinho, Ronald A. / Constitutive telomerase expression promotes mammary carcinomas in aging mice. In: Proceedings of the National Academy of Sciences of the United States of America. 2002 ; Vol. 99, No. 12. pp. 8191-8196.
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