@article{e841f9a0d46b4ccb8a2dfcd4a5039195,
title = "Telomerase reactivation following telomere dysfunction yields murine prostate tumors with bone metastases",
abstract = "To determine the role of telomere dysfunction and telomerase reactivation in generating pro-oncogenic genomic events and in carcinoma progression, an inducible telomerase reverse transcriptase (mTert) allele was crossed onto a prostate cancer-prone mouse model null for Pten and p53 tumor suppressors. Constitutive telomerase deficiency and associated telomere dysfunction constrained cancer progression. In contrast, telomerase reactivation in the setting of telomere dysfunction alleviated intratumoral DNA-damage signaling and generated aggressive cancers with rearranged genomes and new tumor biological properties (bone metastases). Comparative oncogenomic analysis revealed numerous recurrent amplifications and deletions of relevance to human prostate cancer. Murine tumors show enrichment of the TGF-β/SMAD4 network, and genetic validation studies confirmed the cooperative roles of Pten, p53, and Smad4 deficiencies in prostate cancer progression, including skeletal metastases. Thus, telomerase reactivation in tumor cells experiencing telomere dysfunction enables full malignant progression and provides a mechanism for acquisition of cancer-relevant genomic events endowing new tumor biological capabilities.",
author = "Zhihu Ding and Wu, {Chang Jiun} and Mariela Jaskelioff and Elena Ivanova and Maria Kost-Alimova and Alexei Protopopov and Chu, {Gerald C.} and Guocan Wang and Xin Lu and Labrot, {Emma S.} and Jian Hu and Wei Wang and Yonghong Xiao and Hailei Zhang and Jianhua Zhang and Jingfang Zhang and Boyi Gan and Perry, {Samuel R.} and Shan Jiang and Liren Li and Horner, {James W.} and Wang, {Y. Alan} and Lynda Chin and Depinho, {Ronald A.}",
note = "Funding Information: We thank S. Zhou and J.P. Morin for excellent mouse husbandry and care, J. Paik, M. Kim, and H. Ying for helpful discussion. We thank W. Hahn for shRNA constructs. Z.D. was supported by the Damon Runyon Cancer Research Foundation. Y.A.W. was supported by the Multiple Myeloma Research Foundation. This work is supported by NCI R01CA084628 (R.A.D.), U01CA141508 (L.C. and R.A.D.), the Prostate Cancer Foundation (R.A.D. and Z.D.), and DOD W81XWH-07-PCRP-IDA (R.A.D. and Z.D.). R.A.D. was an American Cancer Society Research Professor and supported by the Robert A. and Renee E. Belfer Foundation. The gene signature and technology developed in this paper have been licensed by Metamark GENETICS ( http://www.metamarkgenetics.com/ ). L.C. and R.A.D. are the founders of Metamark GENETICS. Z.D. and C.J.W. are consultants for Metamark GENETICS. ",
year = "2012",
month = mar,
day = "2",
doi = "10.1016/j.cell.2012.01.039",
language = "English (US)",
volume = "148",
pages = "896--907",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "5",
}